U.S. patent number 9,908,971 [Application Number 15/216,573] was granted by the patent office on 2018-03-06 for multi-arm polyethylene glycol derivative, intermediate thereof, and method for producing same.
This patent grant is currently assigned to NOF CORPORATION. The grantee listed for this patent is NOF CORPORATION. Invention is credited to Midori Hirai, Hitoshi Nakatsuhara, Yuji Yamamoto, Hiroki Yoshioka.
United States Patent |
9,908,971 |
Yoshioka , et al. |
March 6, 2018 |
Multi-arm polyethylene glycol derivative, intermediate thereof, and
method for producing same
Abstract
A multi-arm polyethylene glycol derivative having a narrow
molecular weight distribution represented by the formula (1):
##STR00001## wherein, L represents a group selected from a linear
or branched alkylene, arylene, or cycloalkylene group having two or
more carbon atoms and combinations thereof, which may have an ether
bond in a chain; X represents a dehydroxylation residue of a linear
sugar alcohol having 5 or 7 carbon atoms; m is the number of
polyethylene glycol chains bonded to X and represents 4 or 6; n is
the average addition molar number of oxyethylene groups and
represents an integer of 3 to 600; Y represents a single bond or an
alkylene group as further defined herein; and Z represents a
chemically reactive functional group.
Inventors: |
Yoshioka; Hiroki (Kawasaki,
JP), Hirai; Midori (Kawasaki, JP),
Nakatsuhara; Hitoshi (Kawasaki, JP), Yamamoto;
Yuji (Kawasaki, JP) |
Applicant: |
Name |
City |
State |
Country |
Type |
NOF CORPORATION |
Tokyo |
N/A |
JP |
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Assignee: |
NOF CORPORATION (Tokyo,
JP)
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Family
ID: |
49260263 |
Appl.
No.: |
15/216,573 |
Filed: |
July 21, 2016 |
Prior Publication Data
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Document
Identifier |
Publication Date |
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US 20160326317 A1 |
Nov 10, 2016 |
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Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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14389459 |
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9428609 |
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PCT/JP2013/059243 |
Mar 28, 2013 |
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Foreign Application Priority Data
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Mar 30, 2012 [JP] |
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2012-079941 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C08G
65/3322 (20130101); C08G 65/2609 (20130101); C08G
65/33389 (20130101); C08G 65/33368 (20130101); C08G
65/33306 (20130101); C08G 65/2696 (20130101); C08G
65/329 (20130101); C08G 65/33337 (20130101); C08G
2650/30 (20130101) |
Current International
Class: |
C08G
65/329 (20060101); C08G 65/26 (20060101); C08G
65/333 (20060101); C08G 65/332 (20060101) |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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101622295 |
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Jan 2010 |
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CN |
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102361912 |
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Feb 2012 |
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CN |
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1400550 |
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Mar 2004 |
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EP |
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2116561 |
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Nov 2009 |
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EP |
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2 360 203 |
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Aug 2011 |
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EP |
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2415799 |
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Feb 2012 |
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EP |
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2415800 |
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Feb 2012 |
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EP |
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2010-235450 |
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Oct 2010 |
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JP |
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2010-254986 |
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Nov 2010 |
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JP |
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2008/105514 |
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Sep 2008 |
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WO |
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2010114073 |
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Oct 2010 |
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WO |
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2011/093508 |
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Aug 2011 |
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WO |
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2011/162252 |
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Dec 2011 |
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WO |
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2012/133490 |
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Oct 2012 |
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WO |
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Other References
Communication dated Dec. 9, 2015 by the European Patent Office in
related Application No. 13768770.3. cited by applicant .
International Search Report dated May 21, 2013 issued in
International Application No. PCT/JP2013/059243 (PCT/ISA/210).
cited by applicant .
Notification of the First Office Action dated Nov. 6, 2015 by The
State Intellectual Property Office of PR China in related
Application No. 201380018542.5. cited by applicant .
Written Opinion dated May 21, 2013 issued in International
Application No. PCT/JP2013/059243 (PCT/ISA/237). cited by applicant
.
Notice to Submit Response dated Nov. 15, 2017, issued by the Korean
Intellectual Property Office in counterpart Korean Application No.
10-2014-7027529. cited by applicant.
|
Primary Examiner: Aguirre; Amanda L
Attorney, Agent or Firm: Sughrue Mion, PLLC
Parent Case Text
CROSS-REFERENCE TO RELATED APPLICATIONS
This is a Rule 53(b) Divisional application of U.S. application
Ser. No. 14/389,459 filed Sep. 30, 2014, which is a National Stage
of International Application No. PCT/JP2013/059243 filed Mar. 28,
2013, which claims benefit of Japanese Patent Application No.
2012-079941 filed on Mar. 30, 2012, the contents of all of which
are incorporated herein by reference in their entirety.
Claims
The invention claimed is:
1. An intermediate of a multi-arm polyethylene glycol derivative,
which is represented by the following formula (4): ##STR00036##
wherein L represents a group selected from a linear or branched
alkylene group having 2 to 12 carbon atoms, an arylene group having
6 to 12 carbon atoms, or a cycloalkylene group having 5 to 12
carbon atoms and combinations thereof, which may be
alkyleneoxyalkyene or aryleneoxyalkylene in case of an ether bond
in a chain; k represents 1 or 2; n is the average addition molar
number of oxyethylene groups and n represents an integer between 3
and 600.
2. The intermediate according to claim 1, which is represented by
the following formula (5): ##STR00037## wherein L and n are defined
in claim 1.
3. The intermediate according to claim 1, wherein polydispersity
Mw/Mn satisfies the relationship of Mw/Mn.ltoreq.1.05 in gel
permeation chromatography.
4. A method for producing the intermediate according to claim 1,
the method comprising all the steps of the following (A), (B), and
(C) in the order: Step (A): a step of linking two molecules of a
compound represented by the formula (6) to a compound represented
by the formula (7) by an etherification reaction to obtain a
compound represented by the formula (8): ##STR00038## wherein k
represents 1 or 2; A-L-A (7) wherein L represents a group selected
from a linear or branched alkylene group having 2 to 12 carbon
atoms, an arylene group having 6 to 12 carbon atoms, or a
cycloalkylene group having 5 to 12 carbon atoms and combinations
thereof, which may have an ether bond in a chain; and A represents
a halogen atom selected from chlorine, bromine, and iodine or a
sulfone-based protective group; ##STR00039## wherein L represents a
group selected from a linear or branched alkylene group having 2 to
12 carbon atoms, an arylene group having 6 to 12 carbon atoms, or a
cycloalkylene group having 5 to 12 carbon atoms and combinations
thereof, which may be alkyleneoxyalkyene or aryleneoxyalkylene in
case of an ether bond in a chain; and k represents 1 or 2; Step
(B): a step of obtaining a compound represented by the formula (9)
by acid hydrolysis of the compound represented by the formula (8):
##STR00040## wherein L represents a group selected from a linear or
branched alkylene group having 2 to 12 carbon atoms, an arylene
group having 6 to 12 carbon atoms, or a cycloalkylene group having
5 to 12 carbon atoms and combinations thereof, which may be
alkyleneoxyalkyene or aryleneoxyalkylene in case of an ether bond
in a chain; and k represents 1 or 2; Step (C): a step of adding
ethylene oxide to the compound represented by the formula (9) using
one or more compounds selected from the group consisting of
potassium hydroxide, sodium hydroxide, sodium methoxide, metal
sodium, metal potassium, and potassium t-butoxide as a catalyst in
the presence of an organic solvent to obtain an intermediate of a
polyethylene glycol derivative represented by the formula (4):
##STR00041## wherein L represents a group selected from a linear or
branched alkylene group having 2 to 12 carbon atoms, an arylene
group having 6 to 12 carbon atoms, or a cycloalkylene group having
5 to 12 carbon atoms and combinations thereof, which may be
alkyleneoxyalkyene or aryleneoxyalkylene in case of an ether bond
in a chain; k represents 1 or 2; n is the average addition molar
number of oxyethylene groups and n represents an integer between 3
and 600.
Description
TECHNICAL FIELD
The present invention relates to a multi-arm polyethylene glycol
derivative having a narrow molecular weight distribution, an
intermediate thereof, and a method for producing the same.
BACKGROUND ART
A drug delivery system (DDS) has been increasingly used in
therapeutic applications for various diseases as an ideal
administration form of pharmaceutical agents. Especially, there has
been widely investigated a development for improving blood
circulation by modifying a pharmaceutical agent with polyethylene
glycol, and there have been placed on the market pharmaceutical
agents in which a cytokine such as interferon or GCSF is modified
with polyethylene glycol. Heretofore, in polyethylene glycol
derivatives, a type of derivatives having one reactive functional
group at an end of polyethylene glycol is common but, in recent
years, a multi-arm polyethylene glycol in which plural functional
groups are introduced in one molecule has been used. Since the
multi-arm polyethylene glycol has plural reactive points with a
drug, there may be mentioned an advantage that a dose of the drug
per unit weight can be increased. However, in the case where the
polyethylene glycol derivative contains one having a different
number of functional groups, there are contained those in which the
number of the drugs modified with one molecule of polyethylene
glycol is different, so that there arises a problem that the drug
is not homogeneous as a pharmaceutical.
In addition, utilizing high water-solubility and biocompatibility
of polyethylene glycol, there has been also advanced a development
of water-swelling polyethylene glycol hydrogel in which
polyethylene glycol and other molecule are combined. Various
applications of the polyethylene glycol hydrogel has been
investigated in biological and medical fields, for example,
adhesive/hemostatic agents, adhesion prevention agents, carriers
for drug controlled release, regenerative medical materials, and
the like. Also as polyethylene glycol for the hydrogel uses,
multi-arm type having more reactive points is useful for forming a
crosslinked structure with the other molecule. Particularly, in the
case where the hydrogel is used as a carrier for drug controlled
release or a regenerative medical material, a quality of a narrower
molecular weight distribution is desired for strictly controlling
permeation and a diffusion rate of a drug or a protein as a growth
factor of a cell from the gel.
As a raw material for the multi-arm polyethylene glycol, it is
common to use a polyol corresponding to the desired number of
functional groups. For example, ring-opening polymerization of
ethylene oxide is conducted using glycerin or the like for
three-arm one or pentaerythritol or the like for four-arm one as a
raw material. Since these low-molecular-weight raw materials hardly
contain impurities, it is possible to form polyethylene glycol of a
high quality having a relatively narrow molecular weight
distribution.
On the other hand, as six-arm and eight-arm polyethylene glycols,
there have been known those using a polyglycerol such as
tetraglycerin or hexaglycerin as a low-molecular-weight raw
material. The polyglycerol is usually a mixture containing products
having plural degrees of polymerization and/or isomers. Since it is
difficult to purify the mixture into a single component owing to
high polarity, a multi-arm polyethylene glycol of a low quality
having a wide molecular weight distribution is formed when ethylene
oxide is added thereto.
Against such a problem, there has been made an attempt to solve it
by adding ethylene oxide using a low-molecular-weight compound
having a high purity as a raw material. In Patent Document 1,
six-arm and eight-arm polyethylene glycols have been synthesized
using dipentaerythritol and tripentaerythritol as raw materials.
Moreover, in Patent Document 2, a six-arm polyethylene glycol has
been synthesized using sorbitol as a raw material.
PRIOR ART DOCUMENTS
Patent Documents
Patent Document 1: European Patent No. 2360203 Patent Document 2:
U.S. Pat. No. 6,858,736
DISCLOSURE OF THE INVENTION
Problems that the Invention is to Solve
However, these polypentaerythritol and sorbitol, and aforementioned
polyglycerols are all solids having an extremely high polarity,
which have such many hydroxyl groups as 6 to 8 hydroxyl groups.
Therefore, stirring in a reaction vessel becomes insufficient and
thus homogeneous dispersion thereof with a catalyst and ethylene
oxide is not achieved at the addition of ethylene oxide, so that
there is a concern that a homogeneous polymerization does not take
place and a polyethylene glycol having a wide molecular weight
distribution is formed.
As above, although a multi-arm polyethylene glycol derivative
having many branches has become an important material in novel
biological and medical fields without limiting to DDS, the
derivative has not been obtained with a quality of an extremely
narrow molecular weight distribution and by an industrially easily
producible method. Accordingly, it has been desired appearance of
such a multi-arm polyethylene glycol derivative.
An object of the present invention is to provide a multi-arm
polyethylene glycol derivative having a narrow molecular weight
distribution, a method for producing the same, and an intermediate
thereof.
Means for Solving the Problems
As a result of extensive studies for solving the above problem, the
present inventors have found a multi-arm polyethylene glycol
derivative having a novel backbone, a method for producing the
same, and an intermediate thereof, and thus they have accomplished
the invention.
Namely, the invention lies in the following.
[1] A multi-arm polyethylene glycol derivative represented by the
following formula (1):
##STR00002## wherein L represents a group selected from a linear or
branched alkylene, arylene, or cycloalkylene group having two or
more carbon atoms and combinations thereof, which may have an ether
bond in a chain; X represents a dehydroxylation residue of a linear
sugar alcohol having 5 or 7 carbon atoms; m is the number of
polyethylene glycol chains bonded to X and represents 4 or 6; n is
the average addition molar number of oxyethylene groups and n
represents an integer of 3 to 600; Y represents a single bond or an
alkylene group which may have an ester bond, a urethane bond, an
amide bond, an ether bond, a carbonate bond, a secondary amino
group, a urea bond, a thioether bond or a thioester bond in a chain
or at an end; and Z represents a chemically reactive functional
group. [2] The multi-arm polyethylene glycol derivative according
to [1], which is represented by the following formula (2):
##STR00003## wherein L represents a group selected from a linear or
branched alkylene, arylene, or cycloalkylene group having two or
more carbon atoms and combinations thereof, which may have an ether
bond in a chain; k represents 1 or 2; n is the average addition
molar number of oxyethylene groups and n represents an integer
between 3 and 600; Y represents a single bond or an alkylene group
which may have an ester bond, a urethane bond, an amide bond, an
ether bond, a carbonate bond, a secondary amino group, a urea bond,
a thioether bond or a thioester bond in a chain or at an end; and Z
represents a chemically reactive functional group. [3] The
multi-arm polyethylene glycol derivative according to [2], which is
represented by the following formula (3):
##STR00004## wherein L represents a group selected from a linear or
branched alkylene, arylene, or cycloalkylene group having two or
more carbon atoms and combinations thereof, which may have an ether
bond in a chain; n is the average addition molar number of
oxyethylene groups and n represents an integer between 3 and 600; Y
represents a single bond or an alkylene group which may have an
ester bond, a urethane bond, an amide bond, an ether bond, a
carbonate bond, a secondary amino group, a urea bond, a thioether
bond or a thioester bond in a chain or at an end; and Z represents
a chemically reactive functional group. [4] The multi-arm
polyethylene glycol derivative according to any one of [1] to [3],
wherein L is an alkylene group having 3 to 8 carbon atoms. [5] The
multi-arm polyethylene glycol derivative according to [4], wherein
L is an n-butylene group. [6] The multi-arm polyethylene glycol
derivative according to any one of [1] to [5], wherein Z is one or
more groups selected from the group consisting of the following
formula (a), formula (b), formula (c), formula (d), formula (e),
formula (f), formula (g), formula (h), formula (i), formula (j),
formula (k), formula (l), formula (m), formula (n), formula (o),
and formula (p):
##STR00005## ##STR00006## wherein R represents a hydrocarbon group
having 1 to 10 carbon atoms, which may contain a fluorine atom. [7]
The multi-arm polyethylene glycol derivative according to any one
of [1] to [6], wherein polydispersity Mw/Mn satisfies the
relationship of Mw/Mn.ltoreq.1.05 in gel permeation chromatography.
[8] The multi-arm polyethylene glycol derivative according to any
one of [1] to [7], wherein the number m of polyethylene glycol
chains bonded to X is 4. [9] An intermediate of the multi-arm
polyethylene glycol derivative according to [2], which is
represented by the following formula (4):
##STR00007## wherein L represents a group selected from a linear or
branched alkylene, arylene, or cycloalkylene group having two or
more carbon atoms and combinations thereof, which may have an ether
bond in a chain; k represents 1 or 2; n is the average addition
molar number of oxyethylene groups and n represents an integer
between 3 and 600. [10] The intermediate according to [9], which is
represented by the following formula (5):
##STR00008## wherein L represents a group selected from a linear or
branched alkylene, arylene, or cycloalkylene group having two or
more carbon atoms and combinations thereof, which may have an ether
bond in a chain; n is the average addition molar number of
oxyethylene groups and n represents an integer between 3 and 600.
[11] The intermediate according to [9] or [10], wherein
polydispersity Mw/Mn satisfies the relationship of
Mw/Mn.ltoreq.1.05 in gel permeation chromatography. [12] A method
for producing the intermediate according to anyone of [9] to [11],
the method comprising all the steps of the following (A), (B), and
(C) in the order:
Step (A): a step of linking two molecules of a compound represented
by the formula (6) to a compound represented by the formula (7) by
an etherification reaction to obtain a compound represented by the
formula (8):
##STR00009## wherein k represents 1 or 2; A-L-A (7) wherein L
represents a group selected from a linear or branched alkylene,
arylene, or cycloalkylene group having two or more carbon atoms and
combinations thereof, which may have an ether bond in a chain; and
A represents a halogen atom selected from chlorine, bromine, and
iodine or a sulfone-based protective group;
##STR00010## wherein L represents a group selected from a linear or
branched alkylene, arylene, or cycloalkylene group having two or
more carbon atoms and combinations thereof, which may have an ether
bond in a chain; and k represents 1 or 2;
Step (B): a step of obtaining a compound represented by the formula
(9) by acid hydrolysis of the compound represented by the formula
(8):
##STR00011## wherein L represents a group selected from a linear or
branched alkylene, arylene, or cycloalkylene group having two or
more carbon atoms and combinations thereof, which may have an ether
bond in a chain; and k represents 1 or 2;
Step (C): a step of adding ethylene oxide to the compound
represented by the formula (9) using one or more compounds selected
from the group consisting of potassium hydroxide, sodium hydroxide,
sodium methoxide, metal sodium, metal potassium, and potassium
t-butoxide as a catalyst in the presence of an organic solvent to
obtain an intermediate of a polyethylene glycol derivative
represented by the formula (4):
##STR00012## wherein L represents a group selected from a linear or
branched alkylene, arylene, or cycloalkylene group having two or
more carbon atoms and combinations thereof, which may have an ether
bond in a chain; k represents 1 or 2; n is the average addition
molar number of oxyethylene groups and n represents an integer
between 3 and 600.
Advantage of the Invention
The novel multi-arm polyethylene glycol derivative (1) according to
the invention has a hydrophobic linking group having an affinity to
an organic solvent in the backbone. Accordingly, at the time of
ethylene oxide addition, dispersion into an organic solvent is
achieved in spite of the presence of many hydroxyl groups and
thereby the polymerization reaction homogeneously takes place, so
that high-quality one having an extremely narrow molecular weight
distribution can be provided.
Moreover, with regard to the novel multi-arm polyethylene glycol
derivative (1) according to the invention, at the step of
synthesizing a low-molecular-weight raw material that is to be a
raw material, it is possible to purify at a stage of an
intermediate having low polarity and viscosity in which polyols are
protected. Therefore, the purification is more simple and
convenient and the purified low-molecular-weight raw material
hardly contains impurities different in the number of functional
groups, so that high-quality one having an extremely narrow
molecular weight distribution can be provided.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a GPC chart of the compound (I).
FIG. 2 is a GPC chart of the compound (XIII).
MODES FOR CARRYING OUT THE INVENTION
L in the formula (1) of the invention represents a group selected
from a linear or branched alkylene, arylene, or cycloalkylene group
having two or more carbon atoms and combinations thereof, which may
have an ether bond in a chain.
As the alkylene group, there may be mentioned those having 2 to 12
carbon atoms (alkylene groups having more preferably 3 to 8 carbon
atoms, further preferably 4 carbon atoms). Specific examples
thereof include, for example, an ethylene group, a propylene group,
an isopropylene group, an n-butylene group, an s-butylene group, a
t-butylene group, a pentamethylene group, a hexamethylene group, a
heptamethylene group, an octamethylene group, a nonamethylene
group, a decamethylene group, an undecamethylene group, a
dodecamethylene group, and the like.
The arylene group constituting L is a substituted or unsubstituted
arylene group having 6 to 12 carbon atoms and, for example, a
phenylene group, a naphthylene group, an anthrylene group, and the
like may be mentioned. Moreover, as the cycloalkylene group
constituting L, cycloalkylene groups having 5 to 12 carbon atoms
may be mentioned and specific examples thereof include, for
example, a cyclopentylene group, a cyclohexylene group, a
cycloheptylene group, a cyclooctylene group, a cyclononylene group,
a cyclodecylene group, and the like. Furthermore, these groups may
be combined and may have an ether bond in a chain for combination.
For example, an alkyleneoxyalkylene group, an aryloxyalkylene
group, and the like may be mentioned.
In the case where L has less than two carbon atoms, since the
effect as a hydrophobic group is not exhibited, ethylene oxide is
not dispersed in an organic solvent at the time when ethylene oxide
is added and thus there is a concern that a molecular weight
distribution is broadened. Moreover, in the case where L has more
than 12 carbon atoms, since surface active performance of the
molecule increases, there is a concern that an expected performance
is not exhibited in the case where an application as a
pharmaceutical modifier is considered. L is preferably a propylene
group, an isopropylene group, an n-butylene group, an s-butylene
group, a t-butylene group, a pentamethylene group, a hexamethylene
group, a heptamethylene group, or an octamethylene group, and more
preferably an n-butylene group.
X represents a dehydroxylation residue of a linear sugar alcohol
having 5 or 7 carbon atoms. One of the carbon atoms of X is bonded
to L through an ether bond and the remaining carbon atoms are
bonded to the polyethylene glycol chain through an ether bond. At
the step of synthesizing a raw material of the intermediate of the
polyethylene glycol derivative, since it is necessary for the sugar
alcohol to protect, as cyclic acetal(s), the polyol structure other
than one hydroxyl group that is to be bonded to L, X is necessarily
a dehydroxylation residue of a linear sugar alcohol having an odd
number of carbon atoms, i.e., 5 or 7 carbon atoms.
As the linear sugar alcohol having 5 or 7 carbon atoms, for
example, there may be mentioned D-arabinitol, L-arabinitol,
xylitol, ribitol, bolemitol, perseitol, and the like and it is
preferably xylitol. m is the number of polyethylene glycol chains
bonded to X and represents 4 or 6 and is preferably 4. k represents
1 or 2 and is preferably 1.
n is the average addition molar number of oxyethylene groups and n
represents an integer of 3 to 600, and is preferably from 5 to 300,
more preferably from 13 to 250.
Y is a linker between the polyoxyethylene group and the reactive
functional group Z. There is a case where the linker Y does not
contain any atom and the case is defined as a single bond. These
are not particularly limited so long as they are conjugated bonds
and may be any one so long as they are bonds usually used as
linkers but there may be preferably mentioned an alkylene group
alone or an alkylene group which may have an ether bond, an ester
bond, a urethane bond, an amide bond, a carbonate bond, a secondary
amino group, a urea bond, a thioether bond or a thioester bond in
the alkylene chain or at an end thereof. The number of carbon atoms
of the alkylene group is preferably from 1 to 12.
As a preferably example of the alkylene group, a structure like
(y1) may be mentioned. As a preferably example of the alkylene
group having an ether bond, a structure like (y2) may be mentioned.
As a preferably example of the alkylene group having an ester bond,
a structure like (y3) may be mentioned. As a preferably example of
the alkylene group having a urethane bond, a structure like (y4)
may be mentioned. As a preferably example of the alkylene group
having an amide bond, a structure like (y5) may be mentioned. As a
preferably example of the alkylene group having a carbonate bond, a
structure like (y6) may be mentioned. As a preferably example of
the alkylene group having a secondary amino group, a structure like
(y7) may be mentioned. As a preferably example of the alkylene
group having a urea bond, a structure like (y8) may be mentioned.
As a preferably example of the alkylene group having a thioether
bond, a structure like (y9) may be mentioned. As a preferably
example of the alkylene group having a thioester bond, a structure
like (y10) may be mentioned.
##STR00013##
In each formula, s is an integer of 0 to 12. The range of s is from
0 to 12. For example, in the case where it is intended to perform
bonding under a hydrophobic environment like the inside of a
protein, s is preferably large and, in the case where it is
intended to perform bonding under a hydrophilic environment, s is
preferably small.
The symbols s in (y5), (y6), (y7), (y8), (y9), and (y10) may be the
same or different.
Z is not particularly limited so long as it is a functional group
capable of reacting with a hydroxyl group, an amino group, a
mercapto group, an aldehyde, a carboxyl group, a triple bond, or an
azido group to forma chemical bond with another substance. For
example, there may be mentioned functional groups described in
"POLY(ETHYLENE GLYCOL) CHEMISTRY" written by J. Milton Harris,
"Bioconjugate Techniques second edition" (2008) written by Greg T.
Hermanson, and "Pegylated Protein Drug: basic Science and Clinical
Application" (2009) written by Francesco M. Veronese, and the
like.
Further specifically, as Z, there may be mentioned functional
groups containing a carboxylic acid, an active ester, an active
carbonate, an aldehyde, an amine, an oxyamine, a hydrazide, an
azide, an unsaturated bond, a thiol, a dithiopyridine, a sulfone, a
maleimide, a vinylsulfone, an .alpha.-iodoacetyl, an acrylate, an
isocyanate, an isothiocyanate, an epoxide), or the like.
Preferably, Z is one or more groups selected from the group
consisting of the following formula (a), formula (b), formula (c),
formula (d), formula (e), formula (f), formula (g), formula (h),
formula (i), formula (j), formula (k), formula (l), formula (m),
formula (n), formula (o), and formula (p):
##STR00014## ##STR00015## wherein R represents a hydrocarbon group
having 1 to 10 carbon atoms, which may contain a fluorine atom.
In preferable embodiments in the reaction of the compound of the
invention with the other substance, Z is a group represented by the
group (i), (ii), (iii), (iv), (v), or (vi).
Group (i): a functional group capable of reacting with a hydroxyl
group of the other substance
(a), (b), (c), (m) mentioned above
Group (ii): a functional group capable of reacting with an amino
group of the other substance
(a), (b), (c), (d), (e), (m), (n) mentioned above Group (iii): a
functional group capable of reacting with a mercapto group of the
other substance (a), (b), (c), (d), (e), (j), (k), (l), (m), (n),
(o), (p) mentioned above Group (iv): a functional group capable of
reacting with an aldehyde or carboxyl group of the other substance
(f), (g), (h), (k) mentioned above Group (v): a functional group
capable of reacting with a triple bond of the other substance (f),
(g), (h), (i), (k) mentioned above Group (vi): a functional group
capable of reacting with an azido group of the other substance (j)
mentioned above
As the substance that forms a chemical bond with the compound of
the invention, a bio-related substance or a raw material of a
biomaterial. The "bio-related substance" in the invention
specifically includes substances exemplified by an intercellular
communication mediator such as a hormone or a cytokine, an
antibody, an enzyme, an animal cell-constituting substance such as
a phospholipid or a glycolipid, a body fluid-constituting substance
such as blood or lymph but is not limited thereto and also is
intended to include various substances present in a living body of
an organism, substances that are converted into those in a living
body, analogs thereof, or mimics thereof, or substances that
interact with a substance present in a living body to exhibit a
physiological activity or similar substances.
The "biomaterial" in the invention is a material that directly
comes into contact with a living body or comes into contact with a
living cell and a raw material thereof may be an organic or
inorganic material. Specifically, there may be mentioned substances
exemplified by natural polymers such as hyaluronic acid, polyamino
acids, and polysaccharides, synthetic polymers such as polyesters,
polymethyl methacrylate, and polyurethanes, ceramics such as
hydroxyapatite and titanium oxide, and the like but, without
limitation thereto, it is also intended to include substances
having biocompatibility solely or in combination.
Production of Intermediate
The intermediate (4) of the multi-arm polyethylene glycol
derivative of the invention can be, for example, produced as
follows.
An etherification reaction is conducted between two molecules of a
compound in which polyol structures other than one hydroxyl group
of a sugar alcohol represented by the following formula (6) are
protected as cyclic acetals and a compound having two leaving
groups A represented by the formula (7) and only an objective
compound (8) is isolated in a purification step (Step (A)). Then,
the compound is hydrolyzed under acidic conditions to deprotect the
cyclic acetal structures to obtain a compound represented by the
formula (9) (Step (B)). Subsequently, 3 to 600 moles of ethylene
oxide is polymerized to the newly formed hydroxyl group, whereby a
compound represented by the formula (4) can be obtained (Step
(C)).
A reaction path for the compound (4) is shown below.
##STR00016## wherein respective symbols are the same as mentioned
above.
Generally, in the case where a sugar alcohol having 5 to 7 hydroxyl
groups is converted to a cyclic acetal, there is a possibility that
an isomer of the compound of the formula (6), in which a remaining
hydroxyl group is present at a position other than 1-position, may
be formed. However, in the case of using as a raw material a
compound in which the hydroxyl group present at a position other
than 1-position remains, efficiency of etherification using the
compound of the formula (7) is low. Accordingly, it is more
preferred to use the sugar alcohol derivative having a structure of
the formula (6), which selectively has a hydroxyl group at
1-position, as a raw material of the etherification reaction.
As above, by synthesizing a highly pure low-molecular-weight raw
material, which is derivatized from a sugar alcohol, and using it
in the ethylene oxide polymerization reaction, the intermediate (4)
of a multi-arm polyethylene glycol derivative having an extremely
narrow molecular weight distribution and a high quality can be
produced by an industrially suitable method.
By using the thus obtained compound (4) having a narrow molecular
weight distribution and functionalizing it into a chemically
reactive group represented by --Y--Z, the multi-arm polyethylene
glycol derivative of the formula (1) of the invention, in which the
narrow molecular weight distribution is maintained, can be
produced. On this occasion, the molecular weight distribution of
the compound (4) that is an intermediate is maintained in the
compound (1), into which a functional group is introduced, without
large change owing to the high stability of the polyether structure
of the backbone.
Moreover, the compound of the formula (1), in which the functional
group Z is any one of (a) to (p), can be reacted with a bio-related
substance or a raw material of a biomaterial. However, the compound
(1) of the invention can be obtained by further reacting the
compound of the formula (1), in which the functional group Z is any
one of (a) to (p), as an intermediate with another compound. For
example, the compound having a functional group of (a) or (n) can
be obtained using the compound having a functional group of (f) as
an intermediate.
Production of the compound (8) is not particularly limited but is
preferably produced by the following step (A).
Step (A): A Step of Etherification of Two Molecules of the Compound
(6) and the Compound (7) Through the Williamson Reaction
In the compound (7) of the reaction, A is sufficiently a leaving
group and examples thereof include halogen atoms such as chlorine,
bromine, and iodine, sulfone-based leaving groups such as a
methanesulfonyl group, a p-toluenesulfonyl group, and a
trifluoromethanesulfonyl group, and the like. As a base for
etherification, it is sufficient to form an alkali metal alkoxide,
and there may be mentioned potassium t-butoxide, sodium hydride,
potassium hydride, metal sodium, hexamethyldisilazane, potassium
carbonate, and the like. The reaction solvent is not particularly
limited so long as it is an aprotic solvent, and there may be
mentioned tetrahydrofuran, dimethyl ether, methylene chloride,
chloroform, dimethylformamide, toluene, benzene, and the like. More
preferred are toluene and dimethylformamide. In no solvent,
viscosity of the compound (6) is high and stirring efficiency is
lowered, so that there is a concern that efficiency of the
etherification is lowered.
In the crude product after the reaction, impurities such as
vinyl-group bodies formed resulting from occurrence of E2
elimination of the compound (6) and the compound (7) are present.
In case where these impurities are not removed, they are subjected
to de-acetalization in the next step to form impurities having
hydroxyl groups, the number of which is different from that of the
objective compound, causing broadened molecular weight distribution
in the case where ethylene oxide is added. Therefore, it is
preferable to isolate the compound (8) through removal and
purification at this stage. The method for the purification is not
particularly limited but it is preferable to remove the impurities
by a purification method such as liquid separation, column
chromatography, distillation, or supercritical extraction and the
purification is further preferably conducted by liquid separation
and column chromatography. As a support in the case of purification
by the column chromatography, there may be mentioned silica gel,
chemically bonded silica gel, alumina, active carbon, magnesium
silicate, polyamide, and the like but preferred is silica gel. As
an eluent, there may be mentioned hexane, toluene, diethyl ether,
chloroform, dichloromethane, acetone, ethyl acetate, acetonitrile,
ethanol, methanol, acetic acid, and the like and the solvent may be
a mixed solvent thereof and preferably a mixed solvent of hexane
and ethyl acetate.
The deprotection reaction of the cyclic acetal structure following
the etherification is not particularly limited but the production
can be conducted by the following step (B).
Step (B): A Step of Deprotection by Reacting the Cyclic Acetal
Structure of the Compound (8) in an Aqueous Solution in the
Presence of an Acid Catalyst Through an Acid Hydrolysis Reaction to
Produce the Compound (9)
The reaction can be conducted in water or a mixed solvent of a
water-soluble solvent and water. As the water-soluble solvent, for
example, methanol, ethanol, acetonitrile, or the like can be used.
As the acid catalyst, organic acids, inorganic acids, solid acids,
or the like may be mentioned. For example, there may be mentioned
acetic acid, trifluoroacetic acid, and the like as the organic
acids and phosphoric acid, sulfuric acid, hydrochloric acid, and
the like as the inorganic acids, and Amberlyst, Diaion, and Dowex
that are cation exchange resins as the solid acids, but preferred
are the solid acids capable of being removed from the objective
products through filtration alone after the reaction. Reaction
temperature is usually from 20 to 100.degree. C., preferably from
40 to 90.degree. C. Reaction time is preferably from 0.5 to 5
hours.
The ethylene oxide addition polymerization to the compound (9)
having a hydroxyl group newly formed by the deprotection of the
cyclic acetal structure is not particularly limited but preferably,
production can be conducted via the following step (C1) and
subsequently the step (C2).
Step (C1): A Step of Dissolving the Compound (9) in an Aqueous
Solution Containing Preferably from 50 Mol % to 250 Mol % of an
Alkali Catalyst to the Compound, then Adding an Organic Solvent,
and Conducting Azeotropic Dehydration at Preferably from 50 to
130.degree. C. Step (C2): A Step of Reacting Ethylene Oxide to the
Compound (9) at 50 to 130.degree. C. in the Presence of an Organic
Solvent to Obtain the Compound (4)
The alkali catalyst in the step (C1) is not particularly limited
but there may be mentioned metal sodium, metal potassium, sodium
hydride, potassium hydride, sodium hydroxide, potassium hydroxide,
sodium methoxide, potassium methoxide, and the like. As the solvent
for dissolving the alkali catalyst, a protic polar solvent such as
methanol or ethanol can be used in addition to water. The
concentration of the alkali catalyst is preferably from 50 mol % to
250 mol % relative to the compound (9). When it is less than 50% by
mol, the polymerization reaction rate of ethylene oxide is
decreased and thermal history is increased to form impurities such
as terminal vinyl ether bodies and the like, so that it is
advantageous to control the concentration to 50 mol % or more for
producing a high-quality high-molecular-weight polymer. When the
catalyst exceeds 250 mol %, viscosity of the reaction solution is
increased or the solution is solidified at the alcoholate formation
reaction, so that the stirring efficiency is decreased and there is
a tendency that the alcoholate formation is not promoted.
The organic solvent for the azeotropic dehydration is not
particularly limited so long as it is an aprotic solvent such as
toluene, benzene, xylene, acetonitrile, ethyl acetate,
tetrahydrofuran, chloroform, methylene chloride, dimethyl
sulfoxide, dimethylformamide, or dimethylacetamide but toluene
having a boiling point close to that of water is preferred.
Azeotropic temperature is preferably from 50 to 130.degree. C. When
the temperature is lower than 50.degree. C., viscosity of the
reaction solution is increased and moisture tends to remain. Since
the remaining of moisture forms a polyethylene glycol compound
derived from the moisture, molecular weight distribution is
broadened and there is a concern that the quality is lowered. Also,
when the temperature is higher than 130.degree. C., there is a
concern that a condensation reaction occurs. In the case that the
moisture remains, it is preferred to repeat the azeotropic
dehydration repeatedly.
The step (C2) is conducted in an organic solvent. The reaction
solvent is not particularly limited so long as it is an aprotic
solvent such as toluene, benzene, xylene, acetonitrile, ethyl
acetate, tetrahydrofuran, chloroform, methylene chloride, dimethyl
sulfoxide, dimethylformamide, or dimethylacetamide but toluene
easily removable by crystallization and vacuum drying after the
reaction is preferred. Reaction time is preferably from 1 to 24
hours. When the time is shorter than 1 hour, there is a concern
that the catalyst is not completely dissolved. When the time is
longer than 24 hours, there is a concern that the aforementioned
decomposition reaction occurs.
Reaction temperature is preferably from 50 to 130.degree. C. When
the temperature is lower than 50.degree. C., the rate of the
polymerization reaction is low and the thermal history is
increased, so that the quality of the compound (4) tends to be
lowered. Moreover, when the temperature is higher than 130.degree.
C., side reactions such as vinyl etherification of the terminal end
occur during the polymerization and the compound (4) tends to be
lowered. During the polymerization, since the viscosity of the
reaction solution is increased as the molecular weight is
increased, an aprotic solvent, preferably toluene may be
appropriately added.
The step (C2) may be repeated plural times. In that case, the
reaction may be conducted in the same manner as above-described
conditions with adding ethylene oxide to the reaction mixture that
remains in the reaction vessel. By controlling the number of
repetitions, the average addition molar number n can be
controlled.
With regard to the compound (4) of the invention, polydispersity
Mw/Mn from the starting point of elution until the final point of
elution satisfies the relationship of Mw/Mn.ltoreq.1.05 when gel
permeation chromatography is conducted. More preferred is the case
where it satisfies Mw/Mn.ltoreq.1.03.
Also, with regard to the compound of the formula (1) of the
invention to be synthesized using the compound of the formula (4)
as an intermediate, polydispersity Mw/Mn from the starting point of
elution until the final point of elution satisfies the relationship
of Mw/Mn.ltoreq.1.05 when gel permeation chromatography is
conducted. More preferred is the case where it satisfies
Mw/Mn.ltoreq.1.03.
In the case of Mw/Mn>1.05, a polyethylene glycol different in
the number of arms is contained and/or ethylene oxide addition does
not homogeneously take place, so that the case means that the
product is a compound having a broad molecular weight distribution.
In the case of binding it to a bio-related substance, since the
number of modifications with the bio-related substance in one
molecule of polyethylene glycol is different, and in the case of
using it as a raw material of a carrier for drug controlled release
or a hydrogel of a regeneration medicine material, since strict
control of permeation and/or diffusion rate of a substance becomes
difficult, there is a concern that a side effect is caused as a
pharmaceutical and a biomaterial.
The following describe the introduction of reactive groups into the
hydroxyl groups of the compound (4) in detail. In the following
description, the compounds (1) in which functional groups Z are (a)
to (p) are sometimes designated as a (a) body to a (p) body,
respectively or an "amine body (f)" and the like with attaching the
name of the functional group.
[Production Method of the Compound (1) in which Z is (d) or
(m)]
A p-nitrophenyl carbonate body (d) or a sulfonate body (m) can be
obtained by reacting an organic base such as triethylamine,
pyridine, or 4-dimethylaminopyridine or an inorganic base such as
sodium carbonate, sodium hydroxide, sodium hydrogen carbonate,
sodium acetate, potassium carbonate, or potassium hydroxide with
any of the compounds represented by the following general formulae
(d1) and (m1) in an aprotic solvent such as toluene, benzene,
xylene, acetonitrile, ethyl acetate, diethyl ether, t-butyl methyl
ether, tetrahydrofuran, chloroform, methylene chloride, dimethyl
sulfoxide, dimethylformamide, or dimethylacetamide or in no
solvent. Also, the above organic base or inorganic base may not be
used. The use ratio of the organic base or inorganic base is not
particularly limited but is preferably molar equivalent or more to
the hydroxyl group in the compound (4). Moreover, an organic base
may be used as a solvent. W in (d1) or (m1) is a halogen atom
selected from chlorine, bromine, and iodine and is preferably
chlorine. The use ratio of the compound represented by the general
formula (d1) or (m1) is not particularly limited but is preferably
molar equivalent or more to the hydroxyl group in the compound (4),
and further preferably, it is preferred to react them in the range
of molar equivalent to 50 moles. Reaction temperature is preferably
from 0 to 300.degree. C., further preferably from 20 to 150.degree.
C. Reaction time is preferably from 10 minutes to 48 hours, further
preferably from 30 minutes to 24 hours. The formed compound may be
purified by a purification method such as extraction,
recrystallization, adsorption treatment, reprecipitation, column
chromatography, or supercritical extraction.
##STR00017## wherein W represents a halogen atom selected from
chlorine, bromine, and iodine; and R represents a hydrocarbon group
having 1 to 10 carbon atoms, which may contain a fluorine atom.
[Production Method of the Compound (1) in which Z is (o)]
A divinyl sulfone body (o) can be obtained by reacting the compound
(4) with divinyl sulfone in an aprotic solvent such as toluene in
the presence of a base catalyst. The base catalyst may be either an
inorganic base or an organic base and is not particularly limited
and examples thereof include potassium t-butoxide, sodium hydride,
potassium hydride, metal sodium, hexamethyldisilazane, potassium
carbonate, and the like. The use ratio of the base catalyst is not
particularly limited but is preferably used in the range of 0.1 to
50 moles relative to the hydroxyl group of the compound (4). The
use ratio of divinyl sulfone is not particularly limited but is
preferably molar equivalent or more to the hydroxyl group of the
compound (4) and, for preventing formation of a by-product dimmer,
it is preferred to use it an excess amount of 10 equivalents or
more. Reaction temperature is preferably from 0 to 100.degree. C.,
further preferably from 20 to 40.degree. C. Reaction time is
preferably from 10 minutes to 48 hours, further preferably from 30
minutes to 24 hours. The formed compound may be purified by a
purification method such as extraction, recrystallization,
adsorption treatment, reprecipitation, column chromatography, or
supercritical extraction.
[Production Method of the Compound (1) in which Z is (a)]
A carboxyl body (a) can be obtained by reacting the compound (4) or
an amine body (f) to be mentioned below with a dicarboxylic acid
anhydride such as succinic anhydride or glutaric anhydride in an
aforementioned aprotic solvent or no solvent. The use ratio of the
dicarboxylic acid anhydride is not particularly limited but is
preferably molar equivalent or more, further preferably molar
equivalent to 5 moles to the hydroxyl group of the compound (4).
Reaction temperature is preferably from 0 to 200.degree. C.,
further preferably from 20 to 150.degree. C. Reaction time is
preferably from 10 minutes to 48 hours, further preferably from 30
minutes to 12 hours.
For the reaction, there may be used an organic base such as
triethylamine, pyridine, or dimethylaminopyridine or an inorganic
base such as sodium carbonate, sodium hydroxide, sodium hydrogen
carbonate, sodium acetate, potassium carbonate, or potassium
hydroxide as a catalyst. The use ratio of the catalyst is not
particularly limited but is preferably from 0.1 to 50% by mass,
further preferably from 0.5 to 20% by mass relative to the compound
(4). The thus formed compound may be purified by a purification
method such as extraction, recrystallization, adsorption treatment,
reprecipitation, column chromatography, or supercritical extraction
or, in the case of using the compound as a raw material of a
condensation reaction, it may be used as it is.
Also, the carboxyl body (a) can be obtained by reacting the
compound (4) with a halogen-substituted carboxylic acid ester such
as ethyl 6-bromohexanoate or ethyl 7-bromoheptanoate in an
aforementioned aprotic solvent or no solvent. The use ratio of the
halogen-substituted carboxylic acid ester is not particularly
limited but is preferably molar equivalent or more, further
preferably molar equivalent to 30 moles to the hydroxyl group of
the compound (4). Reaction temperature is preferably from 0 to
200.degree. C., further preferably from 20 to 150.degree. C.
Reaction time is preferably from 10 minutes to 48 hours, further
preferably from 30 minutes to 12 hours. For the reaction, there may
be used an organic base such as triethylamine, pyridine, or
dimethylaminopyridine or an inorganic base such as sodium
carbonate, sodium hydroxide, sodium hydrogen carbonate, sodium
acetate, potassium carbonate, or potassium hydroxide as a catalyst.
The use ratio of the catalyst is preferably from 0.1 to 500% by
mass, further preferably from 0.5 to 300% by mass relative to the
compound (4). After etherification, hydrolysis of an ester is
conducted by adding an aqueous solution of sodium hydroxide,
potassium hydroxide, or the like in case of the organic base or
water in case of the inorganic base. Reaction temperature is
preferably from 0 to 100.degree. C., further preferably from 20 to
100.degree. C. Reaction time is preferably from 10 minutes to 48
hours, further preferably from 30 minutes to 12 hours. After the
reaction, neutralization is conducted with hydrochloric acid,
sulfuric acid, or the like. The thus formed compound may be
purified by an aforementioned purification method or, in the case
of using the compound as a raw material of a condensation reaction,
it may be used as it is.
[Production Method of the Compound (1) in which Z is (b)]
A succinimide body (b) can be obtained by subjecting the carboxyl
body (a) to a condensation reaction with N-hydroxysuccinimide in an
aforementioned aprotic solvent or no solvent in the presence of a
condensing reagent such as DCC or EDC. The condensing agent is not
particularly limited but is preferably DCC. The use ratio of DCC is
preferably molar equivalent or more, further preferably molar
equivalent to 5 moles to the carboxyl group. The use ratio of
N-hydroxysuccinimide is preferably molar equivalent or more,
further preferably molar equivalent to 5 moles to the carboxyl
group. Reaction temperature is preferably from 0 to 100.degree. C.,
further preferably from 20 to 80.degree. C. Reaction time is
preferably from 10 minutes to 48 hours, further preferably from 30
minutes to 12 hours. The formed compound may be purified by a
purification method such as extraction, recrystallization,
adsorption treatment, reprecipitation, column chromatography, or
supercritical extraction.
[Production Method of the Compound (1) in which Z is (c)]
A succinimide carbonate body (c) can be obtained by reacting the
compound (4) with an organic base such as triethylamine, pyridine,
or 4-dimethylaminopyridine or an inorganic base such as sodium
carbonate, sodium hydroxide, sodium hydrogen carbonate, sodium
acetate, potassium carbonate, or potassium hydroxide and
N,N'-disuccinimide carbonate in an aforementioned aprotic solvent
or in no solvent. The above-described organic base or inorganic
base may not be used. The use ratio of the organic base or
inorganic base is not particularly limited but is preferably molar
equivalent or more to the hydroxyl group of the compound (4).
Moreover, the organic base may be used as a solvent. The use ratio
of N,N'-disuccinimide carbonate is preferably molar equivalent or
more, further preferably molar equivalent to 5 moles to the
hydroxyl group of the compound (4). Reaction temperature is
preferably from 0 to 100.degree. C., further preferably from 20 to
80.degree. C. Reaction time is preferably from 10 minutes to 48
hours, further preferably from 30 minutes to 12 hours. The formed
compound may be purified by a purification method such as
extraction, recrystallization, adsorption treatment,
reprecipitation, column chromatography, or supercritical
extraction.
[Production Method of the Compound (1) in which Z is (f)]
The amine body (f) can be obtained by adding the compound (4) to
acrylonitrile or the like using an inorganic base such as sodium
hydroxide or potassium hydroxide as a catalyst in a solvent such as
water or acetonitrile to obtain a nitrile body and thereafter
conducting a hydrogenation reaction of the nitrile group under a
nickel or palladium catalyst in an autoclave. The use ratio of the
inorganic base at the time of obtaining the nitrile body is not
particularly limited but is preferably from 0.01 to 50% by mass
relative to the compound (4). The use ratio of acrylonitrile is not
particularly limited but is preferably molar equivalent or more,
further preferably molar equivalent to 50 moles to the hydroxyl
group of the compound (4). Moreover, acrylonitrile may be used as a
solvent. Reaction temperature is preferably from -50 to 100.degree.
C., further preferably from -20 to 60.degree. C. Reaction time is
preferably from 10 minutes to 48 hours, further preferably from 30
minutes to 24 hours. The reaction solvent in the subsequent
hydrogenation reaction of the nitrile body is not particularly
limited so long as it is a solvent that does not participate in the
reaction but is preferably toluene. The use ratio of the nickel or
palladium catalyst is not particularly limited but is from 0.05 to
30% by mass, preferably from 0.5 to 20% by mass relative to the
nitrile body. Reaction temperature is preferably from 20 to
200.degree. C., further preferably from 50 to 150.degree. C.
Reaction time is preferably from 10 minutes to 48 hours, further
preferably from 30 minutes to 24 hours. Hydrogen pressure is
preferably from 2 to 10 MPa, further preferably from 3 to 8 MPa.
Moreover, in order to prevent dimerization, ammonia may be added
into the reaction system. Ammonia pressure in the case of adding
ammonia is not particularly limited but is from 0.1 to 10 MPa,
further preferably from 0.3 to 2 MPa. The formed compound may be
purified by a purification method such as extraction,
recrystallization, adsorption treatment, reprecipitation, column
chromatography, or supercritical extraction.
Alternatively, the amine body (f) can be also obtained by reacting
the sulfonate body (m) with aqueous ammonia. The reaction is
carried out in aqueous ammonia and the concentration of ammonia is
not particularly limited but is preferably in the range of 10 to
40% by mass. The use ratio of aqueous ammonia is preferably from 1
to 300 times relative to the mass of the sulfonate body (m).
Reaction temperature is preferably from 0 to 100.degree. C.,
further preferably from 20 to 80.degree. C. Reaction time is
preferably from 10 minutes to 72 hours, further preferably from 1
to 36 hours.
Moreover, the amine body (f) can be obtained by reacting the
sulfonate body (m) with ammonia in an autoclave. The reaction
solvent is not particularly limited but methanol and ethanol may be
preferably mentioned. The amount of ammonia is preferably from 10
to 300% by mass, further preferably from 20 to 200% by mass
relative to the sulfonate body (m). Reaction temperature is
preferably from 50 to 200.degree. C., further preferably from 80 to
150.degree. C. Reaction time is preferably from 10 minutes to 24
hours, further preferably from 30 minutes to 12 hours. The formed
compound may be purified by the aforementioned purification
method.
Furthermore, the amine body (f) can be also obtained by combining
the compound (4) with phthalimide using the Mitsunobu reaction in
an aprotic solvent, followed by deprotection with a primary amine.
The reaction conditions for the Mitsunobu reaction are not
particularly limited but the reaction solvent is preferably
chloroform or dichloromethane. The use ratio of triphenylphosphine
and an azocarboxylic acid ester is not particularly limited but is
preferably molar equivalent or more, further preferably molar
equivalent to 50 moles to the hydroxyl group of the compound (4).
Reaction temperature is preferably from 0 to 100.degree. C.,
further preferably from 10 to 50.degree. C. Reaction time is
preferably from 10 minutes to 72 hours, further preferably from 30
minutes to 6 hours.
With regard to the deprotection, the primary amine to be used is
not particularly limited but there may be preferably mentioned
ammonia, methylamine, ethylamine, propylamine, butylamine,
pentylamine, hexylamine, cyclohexylamine, ethanolamine,
propanolamine, butanolamine, ethylenediamine, and the like. As a
matter of course, these primary amines may be used as solvents. The
use ratio of the primary amine is not particularly limited but is
preferably molar equivalent or more, further preferably molar
equivalent to 500 moles to the hydroxyl group of the compound (4).
The reaction solvent is not particularly limited but methanol is
preferred. Reaction temperature is preferably from 0 to 100.degree.
C., further preferably from 20 to 80.degree. C. Reaction time is
preferably from 10 minutes to 72 hours, further preferably from 1
to 10 hours. The formed compound may be purified by the
aforementioned purification method.
[Production Method of the Compound (1) in which Z is (g)]
An oxyamine body (g) can be obtained by reacting the active
carbonate body (c) or (d) with a compound (g1) represented by the
following general formula in the presence of a base catalyst such
as triethylemine or pyridine to convert the carbonate body into an
oxyphthalimide body, followed by dephthalimidation in the presence
of a primary amine. The reaction solvent for the oxyphthalimidation
is not particularly limited so long as it is no solvent or a polar
solvent but is preferably dimethylformamide. The use ratio of the
base catalyst is not particularly limited but is preferably molar
equivalent or more, further preferably in the range of molar
equivalent to 20 moles to the active carbonate group. The use ratio
of compound (g1) is preferably molar equivalent or more, further
preferably molar equivalent to 20 moles to the active carbonate
group. Reaction temperature is preferably from 0 to 100.degree. C.,
further preferably from 20 to 80.degree. C. Reaction time is
preferably from 10 minutes to 48 hours, further preferably from 30
minutes to 12 hours. The formed compound may be purified by a
purification method such as extraction, recrystallization,
adsorption treatment, reprecipitation, column chromatography, or
supercritical extraction or may be used in the following step
without purification.
The reaction solvent for the dephthalimidation is not particularly
limited but methanol is preferred. The primary amine to be used is
not particularly limited but there may be preferably mentioned
ammonia, methylamine, ethylamine, propylamine, butylamine,
pentylamine, hexylamine, cyclohexylamine, ethanolamine,
propanolamine, butanolamine, ethylenediamine, and the like. As a
matter of course, these primary amines may be used as solvents. The
use ratio of the primary amine is not particularly limited but is
preferably molar equivalent or more, further preferably molar
equivalent to 50 moles to the active carbonate group. Reaction
temperature is preferably from 0 to 100.degree. C., further
preferably from 20 to 80.degree. C. Reaction time is preferably
from 10 minutes to 48 hours, further preferably from 30 minutes to
12 hours. The formed compound may be purified by the aforementioned
purification method.
##STR00018## (Q represents a linear alkylene group having 1 to 7
carbon atoms.) [Production Method of the Compound (1) in which Z is
(n)]
A maleimide body (n) can be obtained by reacting the amine body (f)
with maleic anhydride in an aforementioned aprotic solvent or no
solvent to obtain a maleamide body and then subjecting it to a
ring-closing reaction using acetic anhydride or sodium acetate as
catalysts. The use ratio of maleic anhydride in the maleamidation
reaction is not particularly limited but is preferably molar
equivalent or more, further preferably molar equivalent to 5 moles
to the amino group. Reaction temperature is preferably from 0 to
200.degree. C., further preferably from 20 to 120.degree. C.
Reaction time is preferably from 10 minutes to 48 hours, further
preferably from 30 minutes to 12 hours. The formed compound may be
purified by a purification method such as extraction,
recrystallization, adsorption treatment, reprecipitation, column
chromatography, or supercritical extraction or may be used in the
following step without purification.
The reaction solvent for the subsequent ring-closing reaction is
not particularly limited but an aprotic solvent or acetic anhydride
is preferred. The use ratio of sodium acetate is not particularly
limited but is preferably molar equivalent or more, further
preferably molar equivalent to 50 moles to the maleamide group.
Reaction temperature is preferably from 0 to 200.degree. C.,
further preferably from 20 to 150.degree. C. Reaction time is
preferably from 10 minutes to 48 hours, further preferably from 30
minutes to 12 hours. The formed compound may be purified by the
aforementioned purification method.
Moreover, the maleimide body (n) can be also obtained by reacting a
compound (n1) represented by the following general formula with the
amine body (f) in an aforementioned aprotic solvent or no solvent.
The use ratio of (n1) is preferably molar equivalent or more,
further preferably molar equivalent to 5 moles to the amino group
(f). Reaction temperature is preferably from 0 to 200.degree. C.,
further preferably from 20 to 80.degree. C. Reaction time is
preferably from 10 minutes to 48 hours, further preferably from 30
minutes to 12 hours. Light may be shielded at the time of the
reaction. The formed compound may be purified by the aforementioned
purification method.
##STR00019## (Q represents a linear alkylene group having 1 to 7
carbon atoms.) [Production Method of the Compound (1) in which Z is
(e)]
An aldehyde body (e) can be obtained by reacting the sulfonate body
(m) with a compound (e1) represented by the following general
formula in an aforementioned aprotic solvent or in no solvent to
obtain an acetal body and then subjecting it to hydrolysis under
acidic conditions. The use ratio of (e1) is preferably molar
equivalent or more, further preferably molar equivalent to 50 moles
to the sulfonate group. (e1) can be prepared from a corresponding
alcohol using metal sodium, metal potassium, sodium hydride,
potassium hydride, sodium methoxide, potassium t-butoxide, or the
like. Reaction temperature is preferably from 0 to 300.degree. C.,
further preferably from 20 to 150.degree. C. Reaction time is
preferably from 10 minutes to 48 hours, further preferably from 30
minutes to 24 hours.
Moreover, in the case of using the compound (e2), the acetal body
can be obtained by converting the hydroxyl group of the compound
(4) into an alcoholate by the aforementioned method and
subsequently conducting a reaction using (e2) in a ratio of molar
equivalent or more, preferably molar equivalent to 100 moles to the
hydroxyl group of the compound (4) in an aprotic solvent or in no
solvent. Reaction temperature is preferably from 0 to 300.degree.
C., further preferably from 20 to 150.degree. C. Reaction time is
preferably from 10 minutes to 48 hours, further preferably from 30
minutes to 24 hours.
Furthermore, in the case of using the compound (e3), the acetal
body can be obtained by reacting the carboxyl body (a), the
succinimide body (b), or the active carbonate body (c), (d), and
(e3). In the reaction with (e3), the solvent is not particularly
limited but the reaction is preferably conducted in an aprotic
solvent. The use ratio of (e3) is preferably molar equivalent or
more, further preferably molar equivalent to 10 moles to the
carboxyl group, the succinimide group, or the active carbonate
group. Reaction temperature is preferably from -30 to 200.degree.
C., further preferably from 0 to 150.degree. C. Reaction time is
preferably from 10 minutes to 48 hours, further preferably from 30
minutes to 24 hours. In the case of using the carboxyl body (a), a
condensing agent such as DCC or EDC may be appropriately used. The
formed compound may be purified by a purification method such as
extraction, recrystallization, adsorption treatment,
reprecipitation, column chromatography, or supercritical extraction
or may be used in the following step without purification.
The subsequent aldehyde formation reaction can be achieved by
transforming the acetal body into a 0.1 to 50% aqueous solution and
hydrolyzing it in an aqueous solution which is adjusted to pH 1 to
4 with an acid such as acetic acid, phosphoric acid, sulfuric acid,
or hydrochloric acid. Reaction temperature is preferably from -20
to 100.degree. C., further preferably from 0 to 80.degree. C.
Reaction time is preferably from 10 minutes to 24 hours, further
preferably from 30 minutes to 10 hours. The reaction may be
conducted with shielding light. The formed compound may be purified
by the aforementioned purification method.
##STR00020## wherein R.sup.2 and R.sup.3 are each a hydrocarbon
group having 1 to 3 carbon atoms and may be the same or different
from each other, and they may form a ring each other; M is sodium
or potassium; A is a halogen atom selected from chlorine, bromine,
and iodine or a sulfone-based protective group; and t is an integer
of 1 to 12. [Production Method of the Compound (1) in which Z is
(k)]
A mercapto body (k) can be obtained by reacting the sulfonate body
(m) with a thiation agent such as thiourea to form a thiazolium
salt and then subjecting it to hydrolysis under alkaline
conditions. The thiation reaction is conducted in acetonitrile or
an alcohol solvent such as methanol, ethanol, or 2-propanol or in
no solvent. The use ratio of the thiation agent is preferably molar
equivalent or more, further preferably in the range of molar
equivalent to 50 moles to the sulfonate group. Reaction temperature
is preferably from 0 to 300.degree. C., further preferably from 20
to 150.degree. C. Reaction time is preferably from 10 minutes to 48
hours, further preferably from 30 minutes to 24 hours. The
subsequent hydrolysis can be achieved by forming a 0.1 to 50%
aqueous solution of the thiazolium salt body and hydrolyzing it in
an aqueous solution which is adjusted to pH 10 to 14 with an alkali
such as sodium hydroxide, potassium hydroxide, or potassium
carbonate. Reaction temperature is preferably from -20 to
100.degree. C., further preferably from 0 to 80.degree. C. Reaction
time is preferably from 10 minutes to 24 hours, further preferably
from 30 minutes to 10 hours. The reaction may be conducted with
shielding light. The formed compound may be purified by a
purification method such as extraction, recrystallization,
adsorption treatment, reprecipitation, column chromatography or
supercritical extraction.
Moreover, the mercapto body (k) may be also obtained by reacting
the sulfonate body (m) with a compound (k1) represented by the
following general formula in an aforementioned aprotic solvent or
in no solvent, followed by decomposition with a primary amine. The
use ratio of (k1) is preferably molar equivalent or more, further
preferably in the range of molar equivalent to 50 moles to the
sulfonate group. Reaction temperature is preferably from 0 to
300.degree. C., further preferably from 20 to 80.degree. C.
Reaction time is preferably from 10 minutes to 48 hours, further
preferably from 30 minutes to 24 hours. The subsequent alkali
decomposition with a primary amine is conducted in an aprotic
solvent or in no solvent. The primary amine to be used is not
particularly limited but there may be preferably mentioned ammonia,
methylamine, ethylamine, propylamine, butylamine, pentylamine,
hexylamine, cyclohexylamine, ethanolamine, propanolamine,
butanolamine, ethylenediamine, and the like. As a matter of course,
these primary amines may be used as solvents. The formed compound
may be purified by the aforementioned purification method.
##STR00021## [Production Method of the Compound (1) in which Z is
(l)]
A dipyridyl disulfide body (l) can be obtained by reacting the
mercapto body (k) with 2,2-dipyridyl disulfide. The reaction
solvent is not particularly limited but the reaction is preferably
conducted in an alcohol solvent such as methanol, ethanol, or
2-propanol. The use ratio of 2,2-dipyridyl disulfide is preferably
molar equivalent or more, further preferably molar equivalent to 50
moles to the mercapto group. Reaction temperature is preferably
from -30 to 100.degree. C., further preferably from 0 to 60.degree.
C. Reaction time is preferably from 10 minutes to 48 hours, further
preferably from 30 minutes to 24 hours. The formed compound may be
purified by a purification method such as extraction,
recrystallization, adsorption treatment, reprecipitation, column
chromatography, or supercritical extraction.
[Production Method of the Compound (1) in which Z is (p)]
An iodoacetyl body (p) can be obtained by reacting the amino body
(f) with iodoacetic anhydride in an aforementioned aprotic solvent
or no solvent. The use ratio of iodoacetic anhydride is not
particularly limited but is preferably molar equivalent or more,
further preferably molar equivalent to 5 moles to the amino group.
Reaction temperature is preferably from 0 to 200.degree. C.,
further preferably from 20 to 120.degree. C. Reaction time is
preferably from 10 minutes to 48 hours, further preferably from 30
minutes to 12 hours. The formed compound may be purified by a
purification method such as extraction, recrystallization,
adsorption treatment, reprecipitation, column chromatography, or
supercritical extraction.
Moreover, the iodoacetyl body (p) can be also obtained by reacting
the amino body (f) with iodoacetic acid in the presence of a
condensing agent such as DCC or EDC in an aforementioned aprotic
solvent or in no solvent. The condensing agent is not particularly
limited but is preferably DCC. The use ratio of DCC is preferably
molar equivalent or more, further preferably molar equivalent to 5
moles to the amino group. The use ratio of iodoacetic acid is not
particularly limited but is preferably molar equivalent or more,
further preferably molar equivalent to 5 moles to the amino group.
Reaction temperature is preferably from 0 to 100.degree. C.,
further preferably from 20 to 80.degree. C. Reaction time is
preferably from 10 minutes to 48 hours, further preferably from 30
minutes to 12 hours. The formed compound may be purified by the
aforementioned purification method.
[Production Method of the Compound (1) in which Z is (h)]
A hydrazide body (h) can be obtained by reacting the succinimide
body (b) or the active carbonate body (c), (d) body with t-butyl
carbazate in an aforementioned aprotic solvent or no solvent,
followed by deprotection of t-butylcarbonyl group. The use ratio of
t-butyl carbazate is not particularly limited but is preferably
molar equivalent or more, further preferably molar equivalent to 10
moles to the succinimide group or the active carbonate group.
Reaction temperature is preferably from 0 to 200.degree. C.,
further preferably from 20 to 80.degree. C. Reaction time is
preferably from 10 minutes to 48 hours, further preferably from 30
minutes to 12 hours. The formed compound may be purified by a
purification method such as extraction, recrystallization,
adsorption treatment, reprecipitation, column chromatography, or
supercritical extraction.
[Production Method of the Compound (1) in which Z is (j)]
An acetylene body (j) can be obtained by reacting the succinimide
body (b) or the active carbonate body (c), (d) body with a compound
(j1) represented by the following general formula in an
aforementioned aprotic solvent or no solvent. The use ratio of (j1)
is not particularly limited but is preferably molar equivalent or
more, further preferably molar equivalent to 50 moles of (j1) to
the succinimide group or the active carbonate group. Reaction
temperature is preferably from 0 to 300.degree. C., further
preferably from 20 to 150.degree. C. Reaction time is preferably
from 10 minutes to 48 hours, further preferably from 30 minutes to
24 hours. The formed compound may be purified by a purification
method such as extraction, recrystallization, adsorption treatment,
reprecipitation, column chromatography, or supercritical
extraction.
##STR00022## wherein u is an integer of 1 to 5; and R.sup.4
represents a hydrogen atom or a hydrocarbon group having 1 to 5
carbon atoms. [Production Method of the Compound (1) in which Z is
(i)]
An azide body (i) can be obtained by reacting the sulfonate body
(m) with sodium azide in an aforementioned aprotic solvent or in no
solvent. The use ratio of sodium azide is preferably molar
equivalent or more, further preferably molar equivalent to moles to
the sulfonate group. Reaction temperature is preferably from 0 to
300.degree. C., further preferably from 20 to 150.degree. C.
Reaction time is preferably from 10 minutes to 48 hours, further
preferably from 30 minutes to 24 hours. The formed compound may be
purified by a purification method such as extraction,
recrystallization, adsorption treatment, reprecipitation, column
chromatography, or supercritical extraction.
EXAMPLES
The following further specifically describe the invention based on
Examples but the invention should not be construed as being limited
thereto. Incidentally, .sup.1H-NMR was used for identification of
compounds in the examples, GPC was used for the molecular weight
distribution, and the molecular weight was determined by measuring
TOF-MS or a hydroxyl value.
<Analytical Method on .sup.1H-NMR>
For .sup.1H-NMR analysis, JNM-ECP400 and JNM-ECP600 manufactured by
JOEL Ltd. were used. Integrated values in NMR measurement values
are theoretical values.
<Analytical Method on GPC>
For GPC analysis, measurement was conducted with a system using any
of DMF, THF, or water as an eluent. Measurement conditions for each
system are shown below.
DMF system . . . GPC system: SHIMADZU LC-10Avp, Eluent: DMF, Flow
rate: 0.7 ml/min, Column: PL gel MIXED-D.times.2 (Polymer
Laboratory), Column temperature: 65.degree. C., Detector: RI,
Sample amount: 1 mg/g, 100 .mu.l
THF system . . . GPC system: SHODEX GPC STSTEM-11, Eluent: THF,
Flow rate: 1 ml/min, Column: SHODEX KF-801, KF-803, KF-804 (I.D. 8
mm.times.30 cm), Column temperature: 40.degree. C., Detector: RI,
Sample amount: 1 mg/g, 100 .mu.l
Water system . . . GPC system: alliance (Waters), Eluent: 100 mM
sodium acetate, 0.02% NaN.sub.3 buffer solution (pH 5.2), Flow
rate: 0.5 ml/min, Column: ultrahydrogel 500+ultrahydrogel 250
(Waters), Column temperature: 30.degree. C., Detector: RI, Sample
amount: 5 mg/g, 20 .mu.l
The GPC measurement value is an analysis value at a main peak with
removing high-molecular-weight impurities and low-molecular-weight
impurities by vertically cutting the baseline from inflection
points of an elution curve. Fraction % represents a ratio of the
main peak relative to the whole peak from the elution start point
to the elution final point, M.sub.n represents number-average
molecular weight, M.sub.w represents weight-average molecular
weight, M.sub.p represents peak top molecular weight, and Mw/Mn
represents polydispersity.
<Molecular Weight Measurement on TOF-MS>
Measurement was conducted using TOF-MS (manufactured by Bruker,
autoflex III) using Dithranol as a matrix and sodium
trifluoroacetate as a salt. For analysis, FlexAnalysis was used and
analysis of molecular weight distribution was conducted on
Polytools. The obtained value at gravity center was described as a
value of molecular weight.
<Molecular Weight Measurement by Hydroxyl Value
Measurement>
According to JIS K1557-1, the hydroxyl value was measured by A
method (acetic anhydride/pyridine). The molecular weight was
calculated from the measured hydroxyl value according to the
following equation. (Molecular
Weight)=56.1.times.1,000.times.8/(Hydroxyl Value)
Incidentally, in the case of a polyethylene glycol derivative, the
value is a theoretical value calculated from the molecular weight
of a hydroxyl body that is an intermediate.
Example 1
Synthesis of Compounds (I), (II), (III), and (IV) (Cases where
L=n-Butylene Group, k=1, Molecular Weight: About 5,000, 10,000,
20,000, 40,000)
##STR00023##
Example 1-1
After 130.3 g (0.56 mol) of 1,2,3,4-diisopropylidenexylitol and
1,650 g of dehydrated toluene were added to a 5,000 ml round-bottom
flask fitted with a thermometer, a nitrogen-inlet tube, and a
stirrer and are dissolved each other under a nitrogen atmosphere,
65.4 g (0.58 mol) of potassium t-butoxide was added thereto,
followed by stirring at room temperature for 30 minutes. On the
other hand, 55.2 g (0.22 mol) of 1,4-butanediol dimethanesulfonate
was dissolved in 660 g of dehydrated DMF and then the solution was
added dropwise into the reaction solution at 40.degree. C. or lower
over a period of 30 minutes. After completion of the stepwise
addition, the temperature was raised to 50.degree. C. and the
reaction was conducted for 6 hours. After completion of the
reaction, the reaction solution was cooled and, after 1,100 g of
ion-exchanged water was added and the whole was stirred for 20
minutes, the whole was allowed to stand and the aqueous layer was
removed. A water-washing operation of adding 830 g of ion-exchanged
water and allowing the whole to stand after stirring was repeated
eight times to remove DMF and unreacted raw materials. After the
water-washing, the organic layer was concentrated and dried with
adding 27.6 g of magnesium sulfate, followed by filtration. The
filtrate was again concentrated and purified by silica gel column
chromatography (Wakogel C-200, Eluent: ethyl acetate:hexane=10:3
(v/v)) to obtain 76.9 g of
1,1'-butylene-bis(2,3,4,5-diisopropylidenexylitol) (V) (0.15 mol;
yield: 66%).
.sup.1H-NMR (CDCl.sub.3, internal standard: TMS)
.delta. (ppm):
1.39, 1.41, 1.42, 1.44 (24H, s, --O--C--CH.sub.3), 1.65 (4H, quint,
--OCH.sub.2CH.sub.2CH.sub.2CH.sub.2--O--), 3.49 (4H, m,
--OCH.sub.2CH.sub.2CH.sub.2CH.sub.2--O--), 3.54-3.58 (4H, m,
--CH.sub.2--O--), 3.85 (2H, t, --CH--O--), 3.89 (2H, dd,
--CH--O--), 4.02-4.07 (4H, m, --CH.sub.2--O--), 4.17 (2H, dd,
--CH--O--)
##STR00024##
Example 1-2
After 76.8 g (0.15 mol) of
1,1'-butylene-bis(2,3,4,5-diisopropylidenexylitol) (V) obtained in
Example 1-1, 456 g of methanol, and 45 g of ion-exchanged water
were added to a 1,000 ml round-bottom flask fitted with a
thermometer, a nitrogen-inlet tube, and a stirrer and are dissolved
each other under a nitrogen atmosphere, 76.4 g of Dowex 50 W-8H
(manufactured by Dow Chemical Company) dispersed in 76 g of
methanol was added thereto and the whole was heated and refluxed to
remove acetone produced as a by-product in an azeotropic manner.
The reaction solution was filtrated and the filtrate was
concentrated to obtain 53.6 g of 1,1'-butylene-bisxylitol (VI)
having the following structure (yield: 66%). .sup.1H-NMR (D.sub.2O,
internal standard: TMS)
.delta. (ppm):
1.66 (4H, quint, --OCH.sub.2CH.sub.2CH.sub.2CH.sub.2--O--),
3.56-3.75 (14H, m, --OCH.sub.2CH.sub.2CH.sub.2CH.sub.2--O--,
--CH.sub.2--O--, --CH--O--), 3.79-3.82 (2H, m, --CH--O--),
3.91-3.93 (2H, m, --CH--O--)
##STR00025##
Example 1-3: Case of Molecular Weight of 5,000
52 g of 1,1'-butylene-bisxylitol (VI) obtained in Example 1-2 was
warmed and, while washing it with 34 g of methanol, was charged
into a 5 L autoclave. Subsequently, 4.9 g of potassium hydroxide
and 10 g of ion-exchanged water were added to a 50 ml beaker to
prepare an aqueous potassium hydroxide solution, which was then
charged into the 5 L autoclave. Then, 500 g of dehydrated toluene
was added thereto and an azeotropic dehydration operation was
repeated three times at 80.degree. C., under slightly reduced
pressure. After the azeotropic dehydration, 1,423 g of dehydrated
toluene was added and, after the inside of the system was replaced
by nitrogen, 654 g (14.85 mol) of ethylene oxide was added at 80 to
150.degree. C. under a pressure of 1 MPa or less, followed by
continuation of the reaction for another 1 hour. After the
reaction, the whole was cooled to 60.degree. C., 945 g of the
reaction solution was taken out of the autoclave, and pH was
adjusted to 7.5 with an 85% aqueous phosphoric acid solution to
obtain the following compound (I). FIG. 1 is a GPC chart of the
compound (I).
.sup.1H-NMR (CDCl.sub.3, internal standard: TMS)
.delta. (ppm):
1.57 (4H, br, --OCH.sub.2CH.sub.2CH.sub.2CH.sub.2--O--), 2.66 (8H,
br, --OH), 3.40 (4H, br, --OCH.sub.2CH.sub.2CH.sub.2CH.sub.2--O--),
3.50-3.81 (430H, m, --CH.sub.2O (CH.sub.2CH.sub.2O).sub.nH,
CHO(CH.sub.2CH.sub.2O).sub.nH,
--CH.sub.2--OCH.sub.2CH.sub.2CH.sub.2CH.sub.2O--CH.sub.2--)
GPC analysis (THF system) . . . main fraction: 100%, Mn: 3,502, Mw:
3,556, Mw/Mn: 1.015, Mp: 3,631
Molecular weight (TOF-MS); 4,991
Molecular weight (hydroxyl value); 5,097
##STR00026##
Example 1-4: Case of Molecular Weight of 10,000
To about 1,345 g of the reaction solution remaining in the reaction
vessel in Example 1-3, 370 g (8.40 mol) of ethylene oxide was added
at 80 to 150.degree. C. under a pressure of 1 MPa or less, followed
by continuation of the reaction for another 1 hour. After the
reaction, the whole was cooled to 60.degree. C., 1,045 g of the
reaction solution was taken out of the vessel, pH was adjusted to
7.5 with an 85% aqueous phosphoric acid solution, and toluene was
removed by distillation to obtain the following compound (II).
.sup.1H-NMR (CDCl.sub.3, internal standard: TMS)
.delta. (ppm):
1.57 (4H, br, --OCH.sub.2CH.sub.2CH.sub.2CH.sub.2--O--), 2.365 (8H,
br, --OH), 3.40 (4H, s, --OCH.sub.2CH.sub.2CH.sub.2CH.sub.2--O--),
3.50-3.81 (878H, m, --CH.sub.2O (CH.sub.2CH.sub.2O).sub.nH,
CHO(CH.sub.2CH.sub.2O).sub.nH,
--CH.sub.2--OCH.sub.2CH.sub.2CH.sub.2CH.sub.2O--CH.sub.2--)
GPC analysis (THF system) . . . main fraction: 99.7%, Mn: 6,846,
Mw: 6,956, Mw/Mn: 1.016, M.sub.p: 7,115
Molecular weight (TOF-MS); 10,033
Molecular weight (hydroxyl value); 10,158
##STR00027##
Example 1-5: Case of Molecular Weight of 20,000
To about 524 g of the reaction solution remaining in the reaction
vessel in Example 1-4, 182 g (4.13 mol) of ethylene oxide was added
at 80 to 150.degree. C. under a pressure of 1 MPa or less, followed
by continuation of the reaction for another 1 hour. After the
reaction, the whole was cooled to 60.degree. C., 620 g of the
reaction solution was taken out of the vessel, pH was adjusted to
7.5 with an 85% aqueous phosphoric acid solution, and toluene was
removed by distillation to obtain the following compound (III).
.sup.1H-NMR (CDCl.sub.3, internal standard: TMS)
.delta. (ppm):
1.57 (4H, br, --OCH.sub.2CH.sub.2CH.sub.2CH.sub.2--O--), 2.57 (8H,
br, --OH), 3.40 (4H, s, --OCH.sub.2CH.sub.2CH.sub.2CH.sub.2--O--),
3.50-3.81 (1774H, m, --CH.sub.2O (CH.sub.2CH.sub.2O).sub.nH,
CHO(CH.sub.2CH.sub.2O).sub.nH,
--CH.sub.2--OCH.sub.2CH.sub.2CH.sub.2CH.sub.2O--CH.sub.2--)
GPC analysis (THF system) . . . main fraction: 99.6%, Mn: 13,064,
Mw: 13,245, Mw/Mn: 1.014, Mp: 13,589
Molecular weight (TOF-MS); 20,083
Molecular weight (hydroxyl value); 20,225
##STR00028##
Example 1-6: Case of Molecular Weight of 40,000
To about 221 g of the reaction solution remaining in the reaction
vessel in Example 1-5, 138 g (3.13 mol) of ethylene oxide was added
at 80 to 150.degree. C. under a pressure of 1 MPa or less, followed
by continuation of the reaction for another 1 hour. After the
reaction, the whole was cooled to 60.degree. C., all the amount of
the reaction solution was taken out of the vessel, pH was adjusted
to 7.5 with an 85% aqueous phosphoric acid solution, and toluene
was removed by distillation to obtain the following compound
(IV).
.sup.1H-NMR (CDCl.sub.3, internal standard: TMS)
.delta. (ppm):
1.57 (4H, br, --OCH.sub.2CH.sub.2CH.sub.2CH.sub.2--O--), 2.589 (8H,
br, --OH), 3.40 (4H, s, --OCH.sub.2CH.sub.2CH.sub.2CH.sub.2--O--),
3.50-3.81 (3598H, m, --CH.sub.2O (CH.sub.2CH.sub.2O).sub.nH,
CHO(CH.sub.2CH.sub.2O).sub.nH,
--CH.sub.2--OCH.sub.2CH.sub.2CH.sub.2CH.sub.2O--CH.sub.2--)
GPC analysis (THF system) . . . main fraction: 97.3%, Mn: 24,050,
Mw: 24,469, Mw/Mn: 1.017, Mp: 25,545
Molecular weight (TOF-MS); 41,450
Molecular weight (hydroxyl value); 38,590
##STR00029##
Example 2: Synthesis of p-Nitrophenyl Carbonate Body (VII): Case of
Molecular Weight of about 5,000
After 20 g (4 mmol) of the compound (I) obtained in the above
Example 1-3 and 80 g of dehydrated toluene were charged into a 200
ml round-bottom flask fitted with a thermometer, a nitrogen-inlet
tube, and a stirrer and PEG was dissolved under a nitrogen
atmosphere, the whole was heated and refluxed at 110.degree. C. to
remove moisture. After cooling, 4.9 g (48 mmol) of triethylamine
and 8.4 g (41.6 mmol) of p-nitrophenyl chloroformate were added
thereto, followed by reaction at 80.degree. C. for 5 hours. After
completion of the reaction, the reaction solution was filtrated and
concentrated. After 60 g of ethyl acetate was added to the
concentrated liquid at 40.degree. C., 40 g of hexane was added
thereto and the whole was stirred for 15 minutes. After it was
allowed to stand, a separating organic layer was removed and ethyl
acetate and hexane were again added, causing layer separation. The
operation of removing low-molecular-weight impurities was repeated
four times. Finally, the solvent was removed under reduced pressure
to obtain the following p-nitrophenyl carbonate body (VII).
.sup.1H-NMR (CDCl.sub.3, internal standard: TMS)
.delta. (ppm):
1.57 (4H, br, --OCH.sub.2CH.sub.2CH.sub.2CH.sub.2--O--), 3.40 (4H,
br, --OCH.sub.2CH.sub.2CH.sub.2CH.sub.2--O--), 3.50-3.81 (414H, m,
--CH.sub.2O (CH.sub.2CH.sub.2O).sub.nH,
CHO(CH.sub.2CH.sub.2O).sub.n--,
--CH.sub.2--OCH.sub.2CH.sub.2CH.sub.2CH.sub.2O--CH.sub.2--), 4.44
(16H, t, --OCH.sub.2CH.sub.2OCOO PhNO.sub.2), 7.40 (16H, d,
--PhNO.sub.2), 8.28 (16H, d, --PhNO.sub.2)
GPC analysis (DMF system) . . . main fraction: 99.2%, Mn: 3,853,
Mw: 3,929, Mw/Mn: 1.020, Mp: 4,005
Molecular weight (TOF-MS); 6,291
##STR00030##
Example 3-1: Synthesis of Cyanoethyl Body: Case of Molecular Weight
of about 10,000
To a 500 ml round-bottom flask fitted with a thermometer, a
nitrogen-inlet tube, and a stirrer, 30 g (3 mmol) of the compound
(II) obtained in the above Example 1-4 and 30 g of ion-exchanged
water were added, and the whole was heated to 40.degree. C. to
achieve dissolution. After the dissolution, the whole was cooled to
10.degree. C. or lower and 3 g of a 50% aqueous potassium hydroxide
solution was added thereto. Subsequently, while the temperature was
kept at 5 to 10.degree. C., 25.5 g (480 mmol) of acrylonitrile was
added dropwise over a period of 2 hours. After completion of the
dropwise addition, the reaction was further conducted for 4 hours
and, after 30 g of ion-exchanged water was added, neutralization
was achieved by adding 1.8 g of an 85% aqueous phosphoric acid
solution. After 45 g of ethyl acetate was added and the whole was
stirred, it was allowed to stand and an upper ethyl acetate layer
was discarded. The extraction with ethyl acetate was repeated nine
times. After completion of the extraction, extraction with 150 g of
chloroform was performed. The resulting chloroform layer was dried
over 15 g of magnesium sulfate and, after filtration, was
concentrated. The concentrated liquid was dissolved with adding 90
g of ethyl acetate, and hexane was added until crystals were
precipitated. The crystals were collected by filtration and again
dissolved in 90 g of ethyl acetate and, after cooling to room
temperature, hexane was added until crystals were precipitated. The
crystals were collected by filtration and dried to obtain the
following cyanoethyl body (VIII).
.sup.1H-NMR (CDCl.sub.3, internal standard: TMS)
.delta. (ppm):
1.57 (4H, br, --OCH.sub.2CH.sub.2CH.sub.2CH.sub.2--O--), 2.63 (16H,
t, --CH.sub.2CH.sub.2CN), 3.39 (4H, br,
--OCH.sub.2CH.sub.2CH.sub.2CH.sub.2--O--), 3.50-3.80 (894H, m,
--CH.sub.2O (CH.sub.2CH.sub.2O).sub.nH,
CHO(CH.sub.2CH.sub.2O).sub.nH,
--CH.sub.2--OCH.sub.2CH.sub.2CH.sub.2CH.sub.2O--CH.sub.2--,
--CH.sub.2CH.sub.2CN)
##STR00031##
Example 3-2: Synthesis of Propylamino Body: Case of Molecular
Weight of about 10,000
To a 1 L autoclave, 13 g of the cyanoethyl body, i.e., the compound
(VIII) obtained in the above Example 3-1, 560 g of toluene, and 1.2
g of nickel (5136p manufactured by N. E. MCAT Company) were added,
and the whole was heated to 60.degree. C. Pressurization was
performed with ammonia until inner pressure reached 1 MPa and
thereafter, hydrogen was introduced to achieve pressurization until
the inner pressure reached 4.5 MPa, followed by reaction at
130.degree. C. for 3 hours. After the reaction, the reaction
solution was cooled to 80.degree. C. and purging with nitrogen was
repeated until ammonia odor disappeared. All the amount of the
reaction solution was taken out and filtrated. After the filtrate
was cooled to room temperature, hexane was added until crystals
were precipitated. The crystals were collected by filtration and
dried to obtain the following amine body (IX).
.sup.1H-NMR (CDCl.sub.3, internal standard: TMS)
.delta. (ppm):
1.57 (4H, br, --OCH.sub.2CH.sub.2CH.sub.2CH.sub.2--O--), 1.72 (16H,
quint, --CH.sub.2CH.sub.2CH.sub.2NH.sub.2), 2.79 (16H, t,
--CH.sub.2CH.sub.2CH.sub.2NH.sub.2), 3.39 (4H, br,
--OCH.sub.2CH.sub.2CH.sub.2CH.sub.2--O--), 3.50-3.80 (894H, m,
--CH.sub.2O (CH.sub.2CH.sub.2O).sub.nH,
CHO(CH.sub.2CH.sub.2O).sub.nH,
--CH.sub.2--OCH.sub.2CH.sub.2CH.sub.2CH.sub.2O--CH.sub.2--,
--CH.sub.2CH.sub.2CH.sub.2NH.sub.2)
GPC analysis (water system) . . . main fraction: 97.9%, Mn: 6,334,
Mw: 6,477, Mw/Mn: 1.022, Mp: 6,571
Molecular weight (TOF-MS); 10,510
##STR00032##
Example 4: Synthesis of Glutaric Acid NHS Body: Case of Molecular
Weight of about 20,000
To a 200 ml round-bottom flask fitted with a thermometer, a
nitrogen-inlet tube, and a stirrer, 25 g (1.25 mmol) of the
compound (III) obtained in the above Example 1-5, 25 mg of BHT, 125
mg of sodium acetate, and 60 g of toluene were added, and PEG was
dissolved under a nitrogen atmosphere. Thereafter, the whole was
heated and refluxed at 110.degree. C. to remove moisture. After
cooling, 1.71 g (15.0 mmol) of glutaric anhydride was added,
followed by reaction at 110.degree. C. for 8 hours. Then, the
reaction solution was cooled to 40.degree. C. and 3.45 g (30.0
mmol) of N-hydroxysuccinimide and 4.33 g (21.0 mmol) of
1,3-dicyclohexylcarbodiimide were added, followed by reaction for 3
hours. After 3 hours, the reaction solution was filtrated and
hexane was added to the filtrate until crystals were precipitated.
The crystals were collected by filtration and dissolved in ethyl
acetate under heating. Thereafter, hexane was added until crystals
were precipitated and the crystals were collected by filtration and
dried to obtain the objective compound (X).
.sup.1H-NMR (CDCl.sub.3, internal standard: TMS)
.delta. (ppm):
1.57 (4H, br, --OCH.sub.2CH.sub.2CH.sub.2CH.sub.2--O--), 2.07 (16H,
quint, --CH.sub.2CH.sub.2CH.sub.2C(O)O--), 2.50 (16H, t,
--CH.sub.2CH.sub.2CH.sub.2C(O)O--), 2.72 (16H, t,
--CH.sub.2CH.sub.2CH.sub.2C(O)O--), 2.84 (32H, br,
--C(O)CH.sub.2CH.sub.2C(O)--), 3.40 (4H, br,
--OCH.sub.2CH.sub.2CH.sub.2CH.sub.2--O--), 3.51-3.64 (1758H, m,
--CH.sub.2O (CH.sub.2CH.sub.2O).sub.nH,
CHO(CH.sub.2CH.sub.2O).sub.nH,
--CH.sub.2--OCH.sub.2CH.sub.2CH.sub.2CH.sub.2O--CH.sub.2--), 4.25
(16H, t, --OCH.sub.2CH.sub.2OC(O)--)
GPC analysis (DMF system) . . . main fraction: 97.5%, Mn: 14,711,
Mw: 15,116, Mw/Mn: 1.028, Mp: 15,635
Molecular weight (TOF-MS); 21,926
##STR00033##
Example 5-1: Synthesis of Hexanoic Acid Body: Case of Molecular
Weight of about 40,000
To a 1,000 ml round-bottom flask fitted with a thermometer, a
nitrogen-inlet tube, and a stirrer, the compound (IV) obtained in
Example 1-6, 60 g of flaky potassium hydroxide, and 600 g of
toluene were added, and dissolution was achieved under a nitrogen
atmosphere. Thereafter, 40.2 g (180 mmol) of ethyl 6-bromohexanoate
was added dropwise at 40.degree. C. with stirring over a period of
2 hours. After completion of the dropwise addition, reaction was
carried out for 5 hours. The reaction solution was cooled, 210 g of
water for injection was added, and the temperature was elevated to
70.degree. C., thus conducting a hydrolysis reaction for 2 hours.
The reaction solution was cooled and 96 g of concentrated
hydrochloric acid was added dropwise with stirring under ice
cooling, thereby achieving protonation. After the whole was allowed
to stand, an organic layer was removed and a step of adding 210 g
of ethyl acetate, stirring the whole for 15 minutes, then allowing
it to stand, and again removing an organic layer was repeated three
times. Thereafter, the resulting aqueous layer was extracted with
150 g of chloroform twice and a combined chloroform layer was dried
over 15 g of magnesium sulfate. After the solution was filtrated,
chloroform was concentrated and the concentrate was dissolved under
heating with adding 210 g of ethyl acetate. Then, 120 g of hexane
was added to precipitate crystals. The resulting crystals were
collected by filtration and dissolved under heating with adding 210
g of ethyl acetate. Thereafter, 120 g of hexane was added to
precipitate crystals again. The resulting crystals were collected
by filtration and, after 120 g of hexane was added and the whole
was stirred, the crystals were collected by filtration and dried
under vacuum to obtain 26 g of the following compound
(XI). .sup.1H-NMR (CDCl.sub.3, internal standard: TMS)
.delta. (ppm):
1.42 (16H, quint,
--OCH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2C(O)O--), 1.58-1.68
(36H, m, --OCH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2C(O)O--,
--OCH.sub.2CH.sub.2CH.sub.2CH.sub.2--O--), 2.32 (16H, t,
--OCH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2C(O)O--), 3.40 (4H, br,
--OCH.sub.2CH.sub.2CH.sub.2CH.sub.2--O--), 3.51-3.84 (3614H, m,
--CH.sub.2O(CH.sub.2CH.sub.2O).sub.nH,
CHO(CH.sub.2CH.sub.2O).sub.nH,
--CH.sub.2--OCH.sub.2CH.sub.2CH.sub.2CH.sub.2O--CH.sub.2--,
--OCH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2C(O)O--)
##STR00034##
Example 5-2: Synthesis of Hexanoic Acid NHS Body: Case of Molecular
Weight of about 40,000
To a 200 ml round-bottom flask fitted with a thermometer, a
nitrogen-inlet tube, and a stirrer, 25 g (0.625 mmol) of the
compound (XI) obtained in Example 1-5 and 75 g of toluene were
added, and PEG was dissolved under a nitrogen atmosphere.
Thereafter, 1.23 g (10.5 mmol) of N-hydroxysuccinimide and 2.09 g
(10.0 mmol) of 1,3-dicyclohexylcarbodiimide were added, followed by
reaction at 40.degree. C. for 2 hours. After 2 hours, the reaction
solution was filtrated and hexane was added to the filtrate until
crystals were precipitated. The crystals were collected by
filtration and dissolved in ethyl acetate under heating.
Thereafter, hexane was added until crystals were precipitated and
the crystals were collected by filtration and dried to obtain the
objective compound (XII).
.sup.1H-NMR (CDCl.sub.3, internal standard: TMS)
.delta. (ppm):
1.47 (16H, quint,
--OCH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2C(O)O--), 1.57 (4H, br,
--OCH.sub.2CH.sub.2CH.sub.2CH.sub.2--O--), 1.62 (16H, quint,
--OCH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2C(O)O--), 1.77 (16H,
quint, --OCH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2C(O)O--), 2.61
(16H, t, --OCH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2C(O)O--), 2.84
(32H, br, --C(O)CH.sub.2CH.sub.2C(O)--), 3.40 (4H, br,
--OCH.sub.2CH.sub.2CH.sub.2CH.sub.2--O--), 3.51-3.64 (3614H, m,
--CH.sub.2O(CH.sub.2CH.sub.2O).sub.n, CHO(CH.sub.2CH.sub.2O).sub.n,
--CH.sub.2--OCH.sub.2CH.sub.2CH.sub.2CH.sub.2O--CH.sub.2--,
--OCH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2C(O)O--)
GPC analysis (DMF system) . . . main fraction: 92.5%, Mn: 28,303,
Mw: 29,013, Mw/Mn: 1.025, Mp: 29,898
Molecular weight (TOF-MS); 43,248
##STR00035##
Comparative Example 1: Synthesis of Hexaglycerol Polyethylene
Glycol Ethers (XIII), (XIV), (XV), (XVI): Cases of Molecular Weight
of about, 5,000, 10,000, 20,000, 40,000
Comparative Example 1-1: Case of Molecular Weight of about
5,000
An aqueous potassium hydroxide solution was prepared by adding 6.7
g of potassium hydroxide, 13.4 g of ion-exchanged water, and 46.9 g
of methanol to a 100 ml beaker. 100 g of hexaglycerin was charged
into a 5 L autoclave and subsequently, the prepared aqueous
potassium hydroxide solution was charged into the 5 L autoclave.
After the inside of the system was replaced by nitrogen, the
pressure was reduced at 90.degree. C. to perform a dehydration
operation over a period of 5 hr. After the inside of the system was
replaced by nitrogen, 886 g (20.1 mmol) of ethylene oxide was added
at 80 to 150.degree. C. under a pressure of 1 MPa or less, followed
by continuation of the reaction for another 1 hour. After the
reaction, the whole was cooled to 60.degree. C., 400 g of the
reaction solution was taken out of the autoclave, and pH was
adjusted to 7.5 with an 85% aqueous phosphoric acid solution to
obtain the compound (XIII).
FIG. 2 is a GPC chart of the compound (XIII). .sup.1H-NMR
(CDCl.sub.3, internal standard: TMS)
.delta. (ppm):
3.45-3.90 (446H, m, --CH.sub.2O(CH.sub.2CH.sub.2O).sub.nH,
--OCH.sub.2CHO(CH.sub.2CH.sub.2O).sub.nH)
GPC analysis (THF system) . . . main fraction: 99.4%, Mn: 2,936,
Mw: 3,218, Mw/Mn: 1.096, Mp: 3,085
Molecular weight measurement (hydroxyl value); 4,847
Comparative Example 1-2: Case of Molecular Weight of about
10,000
To about 582 g of the reaction solution remaining in the reaction
vessel in Comparative Example 1-1, 575 g (13.0 mol) of ethylene
oxide was added at 80 to 150.degree. C. under a pressure of 1 MPa
or less, followed by continuation of the reaction for another 1
hour. After the reaction, the whole was cooled to 60.degree. C.,
500 g of the reaction solution was taken out of the vessel and pH
was adjusted to 7.5 with an 85% aqueous phosphoric acid solution to
obtain the compound (XIV).
.sup.1H-NMR (CDCl.sub.3, internal standard: TMS)
.delta. (ppm):
3.45-3.90 (894H, m, --CH.sub.2O(CH.sub.2CH.sub.2O).sub.nH,
--OCH.sub.2CHO(CH.sub.2CH.sub.2O).sub.nH)
GPC analysis (THF system) . . . main fraction: 98.8%, Mn: 5,864,
Mw: 6,257, Mw/Mn: 1.067, Mp: 6,192
Molecular weight measurement (hydroxyl value); 10,074
Comparative Example 1-3: Case of Molecular Weight of about
20,000
To about 657 g of the reaction solution remaining in the reaction
vessel in Comparative Example 1-2, 655 g (14.9 mol) of ethylene
oxide was added at 80 to 150.degree. C. under a pressure of 1 MPa
or less, followed by continuation of the reaction for another 1
hour. After the reaction, the whole was cooled to 60.degree. C.,
600 g of the reaction solution was taken out of the vessel and pH
was adjusted to 7.5 with an 85% aqueous phosphoric acid solution to
obtain the compound (XV).
.sup.1H-NMR (CDCl.sub.3, internal standard: TMS)
.delta. (ppm):
3.45-3.90 (1790H, m, --CH.sub.2O(CH.sub.2CH.sub.2O).sub.nH,
--OCH.sub.2CHO(CH.sub.2CH.sub.2O).sub.nH)
GPC analysis (THF system) . . . main fraction: 96.7%, Mn: 11,188,
Mw: 11,898, Mw/Mn: 1.064, Mp: 11,429
Molecular weight measurement (hydroxyl value); 19,598
Comparative Example 1-4: Case of Molecular Weight of about
40,000
To about 712 g of the reaction solution remaining in the reaction
vessel in Comparative Example 1-3, 708 g (16.1 mol) of ethylene
oxide was added at 80 to 150.degree. C. under a pressure of 1 MPa
or less, followed by continuation of the reaction for another 1
hour. After the reaction, the whole was cooled to 60.degree. C.,
all the amount of the reaction solution was taken out of the vessel
and pH was adjusted to 7.5 with an 85% aqueous phosphoric acid
solution to obtain the compound (XVI).
.sup.1H-NMR (CDCl.sub.3, internal standard: TMS)
.delta. (ppm):
3.45-3.90 (3614H, m, --CH.sub.2O(CH.sub.2CH.sub.2O).sub.nH,
--OCH.sub.2CHO(CH.sub.2CH.sub.2O).sub.nH)
GPC analysis (THF system) . . . main fraction: 98.6%, Mn: 20,303,
Mw: 21,342, Mw/Mn: 1.051, Mp: 22,076
Molecular weight measurement (hydroxyl value); 35,900
Comparative Example 2-1: Synthesis of Cyanoethyl Body: Case of
Molecular Weight of about 10,000
To a 3,000 ml round-bottom flask fitted with a thermometer, a
nitrogen-inlet tube, and a stirrer, 400 g (40 mmol) of the compound
(XIV) obtained in the above Comparative Example 1-2 and 400 g of
ion-exchanged water were added, and the whole was heated to
40.degree. C. to achieve dissolution. After the dissolution, the
whole was cooled to 10.degree. C. or lower and 40 g of a 50%
aqueous potassium hydroxide solution was added thereto.
Subsequently, while the temperature was kept at 5 to 10.degree. C.,
255 g (4.8 mol) of acrylonitrile was added dropwise over a period
of 2 hours. After completion of the dropwise addition, the reaction
was further conducted for 4 hours and, after 400 g of ion-exchanged
water was added, neutralization was achieved by adding 24 g of an
85% aqueous phosphoric acid solution. After 720 g of ethyl acetate
was added and the whole was stirred, it was allowed to stand and an
upper ethyl acetate layer was discarded. The extraction with ethyl
acetate was repeated nine times. After completion of the
extraction, extraction with 530 g of chloroform was performed. The
resulting chloroform layer was dried over 80 g of magnesium sulfate
and, after filtration, was concentrated. The concentrated liquid
was dissolved with adding 1,000 g of ethyl acetate, and hexane was
added until crystals were precipitated. The crystals were collected
by filtration and again dissolved in 1,000 g of ethyl acetate and,
after cooling to room temperature, hexane was added until crystals
were precipitated. The crystals were collected by filtration and
dried to obtain a cyanoethyl body (XVII).
.sup.1H-NMR (CDCl.sub.3, internal standard: TMS)
.delta. (ppm):
2.63 (16H, t, --CH.sub.2CH.sub.2CN), 3.45-3.80 (910H, m,
--CH.sub.2O (CH.sub.2CH.sub.2O).sub.nH,
--OCH.sub.2CHO(CH.sub.2CH.sub.2O).sub.nH, --CH.sub.2CH.sub.2CN)
Molecular weight measurement (hydroxyl value); 10,498
Comparative Example 2-2: Synthesis of Propylamino Body: Case of
Molecular Weight of about 10,000
To a 1 L autoclave, 75 g of the cyanoethyl body, i.e., the compound
(XVII) obtained in the above Comparative Example 2-1, 510 g of
toluene, and 6.8 g of nickel (5136p manufactured by N. E. MCAT
Company) were added, and the temperature was elevated to 60.degree.
C. Pressurization was performed with ammonia until inner pressure
reached 1 MPa and thereafter, hydrogen was introduced to achieve
pressurization until the inner pressure reached 4.5 MPa, followed
by reaction at 130.degree. C. for 3 hours. After the reaction, the
reaction solution was cooled to 80.degree. C. and purging with
nitrogen was repeated until ammonia odor disappeared. All the
amount of the reaction solution was taken out and filtrated. After
the filtrate was cooled to room temperature, hexane was added until
crystals were precipitated. The crystals were collected by
filtration and dried to obtain an amine body (XVIII).
.sup.1H-NMR (CDCl.sub.3, internal standard: TMS)
.delta. (ppm):
1.77 (16H, quint, --CH.sub.2CH.sub.2CH.sub.2NH.sub.2), 2.74 (16H,
t, --CH.sub.2CH.sub.2CH.sub.2NH.sub.2), 3.62-3.90 (910H, m,
--CH.sub.2O(CH.sub.2CH.sub.2O).sub.nH,
--OCH.sub.2CHO(CH.sub.2CH.sub.2O).sub.nH,
--CH.sub.2CH.sub.2CH.sub.2NH.sub.2)
GPC analysis (water system) . . . main fraction: 96.8%, Mn: 5,832,
Mw: 6,387, Mw/Mn: 1.095, Mp: 5,821
Molecular weight measurement (hydroxyl value); 10,530
Comparative Example 3: Synthesis of Glutaric Acid NHS Body: Case of
Molecular Weight of about 20,000
To a 200 ml round-bottom flask fitted with a thermometer, a
nitrogen-inlet tube, and a stirrer, 100 g (5 mmol) of the compound
(XV) obtained in Comparative Example 1-3, 100 mg of BHT, 500 mg of
sodium acetate, and 150 g of toluene were added, and PEG was
dissolved under a nitrogen atmosphere. Thereafter, the whole was
heated and refluxed at 110.degree. C. to remove moisture. After
cooling, 6.8 g (60 mmol) of glutaric anhydride was added, followed
by reaction at 110.degree. C. for 8 hours. Then, the reaction
solution was cooled to 40.degree. C. and 13.8 g (120 mmol) of
N-hydroxysuccinimide and 17.3 g (84 mmol) of
1,3-dicyclohexylcarbodiimide were added, followed by reaction for 3
hours. After 3 hours, the reaction solution was filtrated and
hexane was added to the filtrate until crystals were precipitated.
The crystals were collected by filtration and dissolved in ethyl
acetate under heating. Thereafter, hexane was added until crystals
were precipitated and the crystals were collected by filtration and
dried to obtain an objective compound (XIX).
.sup.1H-NMR (CDCl.sub.3, internal standard: TMS)
.delta. (ppm):
2.07 (16H, quint, --CH.sub.2CH.sub.2CH.sub.2C(O)O--), 2.48 (16H, t,
--CH.sub.2CH.sub.2CH.sub.2C(O)O--), 2.72 (16H, t,
--CH.sub.2CH.sub.2CH.sub.2C(O)O--), 2.84 (32H, br,
--C(O)CH.sub.2CH.sub.2C(O)--), 3.51-3.64 (1774H, m, --CH.sub.2O
(CH.sub.2CH.sub.2O).sub.nH,
--OCH.sub.2CHO(CH.sub.2CH.sub.2O).sub.nH), 4.25 (16H, t,
--OCH.sub.2CH.sub.2OC(O)--)
GPC analysis (DMF system) . . . main fraction: 97.7%, Mn: 16,386,
Mw: 18,001, Mw/Mn: 1.099, Mp: 16,701
Molecular weight measurement (hydroxyl value); 21,286
FIGS. 1 and 2 show results of analyzing the compound (I) obtained
in Example 1-3 and the compound (VIII) obtained in Comparative
Example 1-1 on GPC. Moreover, Table 1 summarizes results of
polydispersity (Mw/Mn) of the main fraction obtained from GPC
analysis in each of Examples 1-3 to 6, 3-2, and 4 and Comparative
Examples 1-1 to 4, 2-2, and 3.
As shown in FIGS. 1 and 2 and Table 1, the multi-arm polyethylene
glycol derivatives of the invention and intermediates thereof have
a small polydispersity, so that it is shown that the molecular
weight distribution is extremely narrow. On the other hand, the
multi-arm polyethylene glycols synthesized from hexaglycerin have a
very large polydispersity, so that it is shown that they are
polyethylene glycols having a broad molecular weight
distribution.
TABLE-US-00001 TABLE 1 Molecular End functional Compound weight
group Mw/Mn Example 1-3 (I) 5,000 Hydroxyl group 1.016 Comparative
(XIII) 1.096 Example 1-1 Example 1-4 (II) 10,000 1.016 Comparative
(XIV) 1.067 Example 1-2 Example 1-5 (III) 20,000 1.014 Comparative
(XV) 1.064 Example 1-3 Example 1-6 (IV) 40,000 1.017 Comparative
(XVI) 1.051 Example 1-4 Example 3-2 (IX) 10,000 Propylamino 1.022
Comparative (XVIII) group 1.095 Example 2-2 Example 4 (X) 20,000
Glutaric acid 1.028 Comparative (XIX) NHS group 1.099 Example 3
While the invention has been described in detail and with reference
to specific embodiments thereof, it will be apparent to one skilled
in the art that various changes and modifications can be made
therein without departing from the spirit and scope thereof.
* * * * *